interactions and incompatibilities of pharmaceutical
TRANSCRIPT
![Page 1: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/1.jpg)
Review Paper
Interactions and incompatibilities of pharmaceutical excipientswith active pharmaceutical ingredients: a comprehensivereview.
Sonali S. Bharate, Sandip B. Bharate and Amrita N. Bajaja* b c
P.E. Society’s Modern College of Pharmacy (For Ladies), Borhadewadi, At/Post- Moshi, Tal-Haweli, Dist- Pune, Maharashtra –a
412105, IndiaSTES’s Sinhgad College of Pharmacy, Off Sinhgad Road, Vadgaon (Budruk), Pune-411041, Indiab
C.U. Shah College of Pharmacy, S.N.D.T. Women’s University, Juhu Tara Road, Santacruz (E), Mumbai, Maharashtra-400049, Indiac
Received: 05 March 2010; Accepted: 03 November 2010
ABSTRACT
Studies of active drug/excipient compatibility represent an important phase in the preformulationstage of the development of all dosage forms. The potential physical and chemical interactionsbetween drugs and excipients can affect the chemical nature, the stability and bioavailability of drugsand, consequently, their therapeutic efficacy and safety. The present review covers the literaturereports of interaction and incompatibilities of commonly used pharmaceutical excipients withdifferent active pharmaceutical ingredients in solid dosage forms. Examples of active drug/excipientinteractions, such as transacylation, the Maillard browning reaction, acid base reactions and physicalchanges are discussed for different active pharmaceutical ingredients belonging to different thera-peutic categories viz antiviral, anti-inflammatory, antidiabetic, antihypertensive, anti-convulsant, an-tibiotic, bronchodialator, antimalarial, antiemetic, antiamoebic, antipsychotic, antidepressant, anti-cancer, anticoagulant and sedative/hypnotic drugs and vitamins. Once the solid-state reactions of apharmaceutical system are understood, the necessary steps can be taken to avoid reactivity and imp-rove the stability of drug substances and products.
KEY WORDS: Incompatibility, interaction, active pharmaceutical ingredient, excipients, lactose, magnesium stearate
INTRODUCTION
Preformulation is the first step in the rationalformulation of an active pharmaceuticalingredient (API). It is an investigation of thephysical-chemical properties of the drug subs-tance, alone and in combination with
excipients. Assessment of possible incom-patibilities between the drug and differentexcipients is an important part of pre-formulation. The formulation of a drug subs-tance frequently involves it being blended withdifferent excipients to improve manufac-turability, and to maximize the product’s abilityto administer the drug dose effectively.Excipients are known to faci l itateadministration and modulate release of theactive component. They can also stabilize itagainst degradation from the environment.
Corresponding author: Dr. Sonali S. Bharate, Assistant Professor, P.E.*
Society’s Modern College of Pharmacy (For Ladies), Borhadewadi,At/Post- Moshi, Tal- Haweli, Dist- Pune, Maharashtra – 412105, India, Email: [email protected]
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 3
![Page 2: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/2.jpg)
Review Paper
Most excipients have no direct pharmacologicalaction but they can impart useful properties tothe formulation. However, they can also giverise to inadvertent and/or unintended effectssuch as increased degradation of the drug.Physical and chemical interactions betweendrugs and excipients can affect the chemicalnature, the stability and bioavailability of drugproducts, and consequently, their therapeuticefficacy and safety (1).
There have been several approaches proposedthat satisfy the requirements of a drug-excipientchemical compatibility screen. The mostresource sparing of these approaches iscomputational, where drug-excipient chemicalcompatibility can be predicted. This requires acomprehensive database of reactive functionalgroups for both drugs and excipients, com-bined with an in-depth knowledge of excipientsand their potential impurities. Such an app-roach provides a rapid analysis and requires nobulk substance. However, there are inherentrisks with using this computational approach asthe sole source of information.
Binary mixture compatibility testing is anothercommonly used method. In this approach,binary (1:1 or customized) mixtures of the drugand excipient, with or without, added water andsometimes compacted or prepared as slurries,are stored under stressed conditions (alsoknown as isothermal stress testing (IST)) andanalyzed using a stability-indicating method,e.g. high performance liquid chromatography(HPLC). The water slurry approach allows thepH of the drug-excipient blend and the role ofmoisture to be investigated. Alternatively,binary mixtures can be screened using otherthermal methods, such as differential scanningcalorimetry (DSC) (2, 3). DSC is currently theleading technique in this field (4). The mainbenefit of DSC, rather than stressed storagemethods, is its ability to quickly screen potentialexcipients for incompatibilities derived fromthe appearance, shifts or disappearances ofpeaks and/or variations in the corresponding ÄH (enthalpy of transition) (5). Other featuressuch as low sample consumption also makes it
an attractive method. Although DSC isunquestionably a valuable technique, interpret-nation of the data may not be straightforward.In this method, the sample is exposed to hightemperatures (up to 300°C or more), which inreality is not experienced by the dosage form.Thus, DSC results should be interpretedcarefully, as the conclusions based on DSCresults alone can be often misleading and in-conclusive. Therefore results obtained withDSC should always be confirmed with IST.
IST involves storage of drug-excipient blendswith, or without moisture, at elevated tem-pertures for a specific period of time (typically3–4 weeks) to accelerate drug degradation andinteraction with excipients. The samples arethen visually observed for any changes in coloror physical characteristics, and the drugcontent, along with any degradants, is deter-mined quantitatively (6). Although more useful,the disadvantage with this method is that it istime consuming and requires quantitativeanalysis using e.g. HPLC. Ideally, both tech-piques, DSC and IST should be used incombination for the selection of excipients.Similarly, isothermal micro calorimetry is a po-pular method for detecting changes in the solidstate of drug-excipient mixtures throughchanges in heat flux (7). The results from usingthermal techniques can be indicative of whet-her formulations are stable, but reveal noinformation concerning the cause or nature ofany incompatibility. Techniques such as hotstage microscopy and scanning electronmicroscopy can be used in conjunction withDSC to determine the nature of an apparentincompatibility (8). These techniques study themorphology of the drug substance and candetermine the nature of phys ica ltransformations, thus indicating the type ofincompatibility that has occurred (4). A moredefinitive result would be obtained using e.g.HPLC or HPLC-MS/MS. It is well known thatthe chemical compatibility of an API in a binarymixture may differ from that of a multi-component prototype formulation. An alterna-tive is to test “prototype” formulations. Theamount of API in the blend can be modified
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 4
![Page 3: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/3.jpg)
Review Paper
according to the anticipated drug-excipientratio in the final compression blend (9).
There are several examples of formulationinstability resulting from solid–solid interac-tions (10, 11). Certain classes of compounds areknown to be incompatible with particularexcipients (12). Therefore knowledge of thechemistry of the drug substance and excipientscan often minimize formulation surprises. Heatand water are the primary catalysts for drug-excipient interactions and play a critical role inthe degradation of a drug substance (13). Themajority of ‘small molecule’ API instabilityreactions occur via hydrolysis, oxidation andMaillard reaction. The moisture content of thedrug and excipients plays a critical role in theirincompatibility. Heat and moisture acceleratemost reactions, even if moisture is not involvedin the reaction scheme, since moisture bringsmolecules closer together, and heat alwaysincreases the reaction rate. The incompatibilitybetween a drug and an excipient per se, and thatwhich occurs between a drug and moisture/water activity due to the ability of the excipientto absorb moisture, represents two differentkinds of incompatibilities. Excipients such asstarch and povidone may possess a high watercontent (the equilibrium moisture content ofpovidone is about 28% at 75% relative humi-dity), which can increase drug degradation. Themoisture level will affect the stability dependingon how strongly it is bound and whether it cancome into contact with the drug (14). It isgenerally recognized that aspirin is incom-patible with magnesium salts. Higher moisturecontents and humidity accelerate thedegradation even further (14). Many differentmoisture mediated degradation mechanismsexist, but those mediated by surface moistureappear to be the most common (15).Consequently it is important that stress met-hods incorporate water to encourage the for-mation of all possible impurities. The way inwhich water facilitates degradation is not fullyunderstood, but work carried out by Kontnyet al. (15) has confirmed its importance. Degra-dation problems can, therefore, be difficult toavoid because water often cannot be entirely
excluded from drug product formulations.Many excipients are hygroscopic, (16, 17) andabsorb water during manufacturing, forexample during wet granulation. Depending onthe degree of hydrolytic susceptibility, differentapproaches to tablet granulation can be used tominimize hydrolysis. For compounds such asacetylsalicylic acid that are readily hydrolysable,direct compression or dry granulation is pre-ferable, to wet granulation. However drug-excipient incompatibility may still occur.
Chemical interaction between the drug andexcipients may lead to increased decom-position. Stearate salts (e.g. magnesium stearate,sodium stearate) should be avoided as tabletlubricants if the API is subject to hydrolysis viaion-catalyzed degradation. Excipients generallycontain more free moisture than the drugsubstance (16), and in an attempt to obtain themost thermodynamically stable state, water isable to equilibrate between the various compo-nents (18). Formulation can, therefore, poten-tially expose the drug substance to higher levelsof moisture than normal, which greatlyincreases the possibility of even stable com-pounds degrading. In selecting excipients, it isprobably best to avoid hygroscopic excipientswhen formulating hydrolytically labile com-pounds, although examples exist where thedrug is deliberately formulated with over-driedhygroscopic excipients (e.g. Starch 1500) whichact as a moisture scavenger to prevent the drugfrom coming into contact with water.
One of the most effective ways to stabilize apH sensitive drug is through the adjustment ofthe microscopic pH of the formulation. Ex-cipients with high pH stability and bufferingagents are recommended. Humidity is anothermajor determinant of product stability in soliddosage forms. Elevation of relative humidityusually decreases the stability, particularly fordrugs that are highly sensitive to hydrolysis. Forexample, nitrazepam in the solid state showed alinear relationship between the logarithm of therate constant for the decomposition of the drugat different relative humidities (19). In addition,increased humidity can also accelerate the
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 5
![Page 4: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/4.jpg)
Review Paper
degradation process by facilitating interactionwith excipients (20, 21). Molecular mobility isalso responsible for solid-solid reactions (22-24). Systems with enhanced mobility have morereactivity. Mechanical stress is also expected toaccelerate such reactions by creating a largersurface area, increasing the number of defects,and increasing the amount of amorphousmaterial (10).
Oxidation reactions are complex and it can bedifficult to understand the reaction mechanism.The best approach is to avoid excipientscontaining oxidative reactants such as peroxidesand fumed metal oxides like fumed silica andfumed titanium dioxide. Excipients such aspovidone and polyethylene glycols (PEGs) maycontain organic peroxides as synthetic by-products which are typically more reactive thanhydrogen peroxide. Although most compendialexcipients have limits on metals, free ethyleneoxide or other oxidizing agents via the peroxideor iodine value there are still some instances ofoxidative degradation of drug due to presenceof reactive peroxides in excipients such aspovidone. For example, Hartauer et al. (2000)reported oxidative degradation of RaloxifeneH.L. occurring via peroxide impurities inpovidone (25). Thus, it is important to under-stand the purity and composition of theexcipient prior to formulation.
Aldehyde-amine addition is another importanttype of reaction, which is responsible forincompatibility between excipients comprisingreducing sugars (e.g. lactose, dextrose) andamine-containing drugs. Aldehyde-amine addi-tion leads to the formation of a Schiff base,which further cyclizes to form a glycosaminefollowed by an Amadori rearrangement (26,27). This sequence of reactions is called theMaillard reaction, and is responsible for a largenumber of incompatibilities between APIs andexcipients.
Monkhouse (28) listed common solid-stateincompatibilities as shown in Table 1.
Table 1 List of common solid-state incompatibilities
Functional Group (Example of API)
Incompatible with Type of Reaction Reference
Primary amine (e.g.Acyclovir)
Mono and disaccharides(e.g. lactose)
Maillard reaction (26, 29)
Esters (e.g.Moexipril)
Basic components (e.g.magnesium hydroxide)
Ester hydrolysis (30)
Lactone (e.g.Irinotecan HCl)
Basic components (e.g.magnesium hydroxide)
Ring opening(hydrolysis)
(31)
Carboxyl Bases Salt formation (28, 32)
Alcohol (e.g.Morphine)
OxygenOxidation toaldehydes andketones
(33, 34)
Sulfhydryl (e.g.Captopril)
Oxygen Dimerization (33, 34)
Phenol Metals, polyplasdone Complexation (28, 32)
Gelatin Cationic surfactants Denaturation (28, 32)
This present review discusses incompatibilitiesof ‘small molecule’ API’s associated withdifferent pharmaceutical excipients as sum-marized in Table 2. Incompatibilities of APIswith different pharmaceutical excipients arediscussed below in subsequent sections relatingto excipient types as follows: Saccharides, Stea-rates, Polyvinylpyrrolidone, Dicalcium phos-phate dihydrate, Eudragit polymers, Celluloses,Polyethylene glycol, Polysorbate 80, Sodiumlauryl sulfate, Chitosan, Magnesium oxide, Sili-con dioxide, Carbonates, and Miscellaneous.
Saccharides
Lactose is perhaps one of the most commonlyused excipients in pharmaceutical oral dosageforms (tablets) and, is in its crystalline form,generally considered to be least reactive. Blaugand Huang (99) reported that, crystallinelactose, rather than, amorphous lactose causeda problem in interaction of dextroamphetaminesulfate with spray dried lactose. Lactose is areducing disaccharide and reactions between itand drugs containing amino groups have beenreported. This interaction is shown in Figure 1.This sequence of such reaction is referred to asthe Maillard reaction (26).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 6
![Page 5: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/5.jpg)
Review Paper
Table 2 A list of excipients and their incompatibilities with API’s belonging to different therapeutic classes
Excipient API and its Therapeutic Class
Saccharides
(A) Lactose
Acyclovir (29) - Antiviral; Aceclofenac (35) and Ketoprofen (36-38) - Anti-inflammatory; Metformin (29)-Antidiabetic; Amlodipine (39), Ceronapril (40), Lisinopril (41) and Oxprenolol (42) - Antihypertensive; Fluconazole(43) - Antifungal; Primaquine (44) - Antimalarial; Promethazine (45) - Antiemetic; Fluoxetine (46) and SeproxetineMaleate (47) – Antidepressant; Picotamide (48) – Anticoagulant; Etamsylate (43) - Antihemorrhagic; Aminophylline(49) and Clenbuterol (50) – Bronchodialator; Baclofen (51)- CNS Drug; Ranitidine (52) – GI Agent; Doxylamine (53)– Antihistaminic; Thiaminechloride HCL (54) – Vitamin; Pefloxacin (55) - Antibiotic
(B) Lactose/meglumine/ Tris Buffer Blend Glipizide (56) - Antidiabetic
(C) Mannitol, Pearlitol (80% Mannitol +20% Maize Starch)
Quinapril (9)- Antihypertensive; Primaquine (44)- Antimalarial; R-omeprazole (57) – GI Agent; Promethazine (45) –Antiemetic
(D) Starch Seproxetine Maleate (47) – Antidepressant; Clenbuterol (50) - Bronchodialator
(E) Sodium Starch Glicollate Clenbuterol (50) - Bronchodialator
(F) Dextrose Pefloxacin (55) - Antibiotic
Stearates
(A) Magnesium Stearate
Acyclovir (58) – Antiviral; Aspirin (59-62), Ibuproxam (8), Indomethacin (63, 64) and Ketoprofen (36-38)- Anti-inflammatory; Glipizide (56), Chlorpropamide (65), Glimepiride (66) and Glibenclamide (67) - Antidiabetic; Captopril (68, 69), Fosinopril (40), Moexipril (10, 30, 70), Oxprenolol (42) and Quinapril (9) - Antihypertensive;Cephalexin (71), Erythromycin (72), Nalidixic Acid (73), Oxacillin (74) and Penicillin G (74) - Antibiotic; Primaquine(44)- Antimalarial; Promethazine (45)- Antiemetic; Albendazole (75) - Antiamoebic; â-lapachone (76)- Anticancer;Clopidogrel (77)- Anticoagulant; Doxylamine (53) – Antihistaminic; Temazepam (42) - Hypnotic
(B) Stearic Acid Doxylamine (53)- Antihistaminic
Polyvinyl Pyrolidone (PVP)Indomethacin (63, 64), Ibuproxam (8) and Ketoprofen (36-38) – Anti-inflammatory; Atenolol (63) and Oxprenolol(42)- Antihypertensive; Sulfathiazole (78) – Antibiotic; Haloperidol (79)- Antipsychotic; Ranitidine (52)- GI Agent;Doxylamine (53)- Antihistaminic; Temazepam (42)- Hypnotic; Clenbuterol (50) – Bronchodialator
Dicalcium Phosphate Dihydrate
(DCPD)
Ceronapril (40), Oxprenolol (42) and Quinapril (9)- Antihypertensive; Metronidazole (80) – Antiamoebic; â-lapachone (76) and Parthenolide (81)- Anticancer; Famotidine (82)- GI Agent; Temazepam (42) - Hypnotic
Eudragit Polym ers
(A) Eudragit RS and Rl Diflunisal (83, 84), Flurbiprofen (83, 84) and Piroxicam (83, 84) – Anti-inflammatory
(B) Eudragit RL100 Ibuprofen (85) (86)– Anti-inflammatory
(C) Eudragit E100 Ranitidine (52) – GI Agent
Celluloses
(A) Microcrystalline Cellulose (MCC),Avicel PH 101
Enalapril (87, 88) – Antihypertensive; Isosorbide Mononitrate (6) – Antiangina; Clenbuterol (50) - Bronchodialator
(B) Cellulose Acetate Isosorbide Mononitrate (6)- Antiangina
(C) Hypromellose Acetate Succinate(HPMCAS)
Dyphylline (89) - Bronchodialator
(D) Hydroxypropyl Cellulose Trichlormethiazide (90) - Diuretic
PEGIbuprofen (91), Ibuproxam (8) and Ketoprofen (36-38)– Anti-inflammatory; Phosphomycin (92) - Antibiotic;Clopidogrel (77)- Anticoagulant
Polysorbate 80 Ibuprofen (91) – Anti-inflammatory
Sodium Lauryl Sulfate Chlorpropamide (65) – Antidiabetic; Clopidogrel (77)– Anticoagulant; Chlordiazepoxide (11, 93) – Hypnotic
Chitosan Diclofenac (11, 94) and Piroxicam (95)– Anti-inflammatory
M agnesium Oxide Ibuprofen (96) – Anti-inflammatory
Silicon Dioxide Enalapril (87, 88) - Antihypertensive
Carbonates
(A) Sodium Carbonate Adefovir Dipivoxil (97) - Antiviral
(B) Sodium Bicarbonate Ibuprofen (96) – Anti-inflammatory
M iscellaneous
(A) Plasdone Glimepiride (66) - antidiabetic
(B) Ascorbic acid Atenolol (63) – antihypertensive
(C) Citric acid Atenolol (63)- antihypertensive
(D) Butylated hydroxyanisole Atenolol (63)- antihypertensive
(E) Succinic acid Phosphomycin (92)- antibiotic
(F) Na dioctylsulfocuccinate Phosphomycin (92) - antibiotic
(G) Ca and Mg salts Tetracyclins (98) - Antibiotic
(H) Talc Seproxetine maleate (47) - antidepressant
(i). Precirol ATO 5 Temazepam (42)- hypnotic
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 7
![Page 6: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/6.jpg)
Review Paper
There are a number of reports of the incom-patibility of lactose with amine-containingAPIs. DSC and FT-IR studies showed thataminophylline, a bronchodilator drug consistingof a purine ring system coupled with anethylenediamine moiety was incompatible withlactose. Brown discoloration appeared insamples containing 1:5 (w/w) mixtures ofaminophylline and lactose following threeweeks of storage at 60°C (100). Another groupof researchers also reported similar findingsfrom stability experiments using aminophyllinecombined with four tablet excipients (cellulosestarch, glucose (dextrose) and lactose) stored at5°C, room temperature (27 ± 3°C), 45°C and indirect sunlight for 30 days. Degradation of thedrug increased with increase in temperature andon exposure to sunlight. The degradation wasparticularly intense in the presence of glucoseand lactose and a change in color from white toyellow occurred in such mixtures. At 45°C andin sunlight both pure drug and its mixtureschanged color during the storage period (49).
Seproxetine, a selective serotonin re-uptakeinhibitor, is a primary amine and an activemetabolite of fluoxetine. Its maleate hemi-hydrate salt demonstrated an incompatibilitywith lactose and starch in a gelatin capsuledosage form. Analogous to a Micheal addition,there is a formation of 1-4 addition productbetween the drug and the maleic acid facilitatedby the free moisture associated with the starch.Formation of the 1,4-addition product wasnoticed in the presence of pregelatinized starchwhile a Maillard reaction product was formed
by interaction of the drug with lactose as shownin Figure 1 (47). The schematic of the interac-tion between saproxetine and maleic acid in thepresence of starch is shown in Figure 2. AnACE inhibitor, ceronapril containing a primaryamine function, also exhibited incompatibilitywith lactose due to a Maillard reaction. HPLCstudies of mixtures of ceronapril with lactoseafter 3 weeks storage at 50ºC showed that theceronapril had degraded by 8.4% (40).
Amlodipine is a dihydropyridine calcium chan-nel blocker containing a primary amine group.It was found to be unstable in a multi-component mixture with lactose, magnesiumstearate and water. Amlodipine besylate glyco-syl was identified as a major reason fordegradation due to a Maillard reaction betweenthe drug and lactose (39). Metformin is a bigua-nide class of antidiabetic drug also containing aprimary amine group. Binary mixtures of met-formin with starch and lactose showed interac-tion upon heating, changing the meltingtemperature of metformin and the accom-panying enthalpy. A change in the meltingtemperature of metformin was observed for allmixtures tested i.e. metformin: starch ratios of2:8; 3:7; 1:1; 7:3 and 8:2. The melting peak formetformin was not visible in the presence oflactose suggesting an interaction between them.Displacement of the melting temperature ofmetformin, for all the metformin–starch mix-tures tested, confirmed the interaction betweenthe two materials. One possible reason for thisinteraction can be a Maillard reaction between
Figure 1 A general Maillard reaction between lactose
and an amine group-containing API Figure 2 Interaction between Seproxetine and maleic
acid in the presence of starch (47).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 8
![Page 7: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/7.jpg)
Review Paper
the lactose carbonyl that can react with anamine group of metformin (101). Acyclovir is apurine class of antiviral drug, again, containinga primary amine group. Results of DSC studiesof physical mixtures of the drug with lactosesuggested an incompatibility, confirmed by li-quid chromatography coupled with mass spect-rometry (LC-MS) which identified the for-mation of a Maillard reaction as shown inFigure 1 (29).
Baclofen is a primary amine used in treatmentof spastic movement disorders. Using LC-MSstudies showed that it was incompatible withlactose as indicated by the formation of a Mail-lard reaction product. Fourier transform infra-red spectroscopic analysis (FTIR) showed theformation of the imine bond, which indicatedthat baclofen, undergoes a Maillard-type reac-tion with lactose (51).
Lactose monohydrate also interacted withmoisture sensitive drugs and affected the stabi-lity of the drug (102). A mixture of thiaminehydrochloride and lactose underwent the Mail-lard reaction forming the N-glycosylamine,which was further converted to the aminoketone via an Amadori rearrangement. Theconfiguration of an á-(spray-dried) lactose andâ-anhydrous lactose was not relevant for theMaillard reaction because the reaction oflactose is believed to occur through an open-chain form. Spray dried lactose also containsamorphous lactose which is important forreactivity (99). Similar changes in spectra werenoticed for binary mixtures of both forms oflactose with thiamine hydrochloride. A changeof tablet color due to the degradation of drugunder accelerated conditions was observed (54).
Although primary amines are the mostcommonly reported substrates for the Maillardreaction, there are also reports of Maillardreactions with secondary amines. Oxprenololhydrochloride (42), fluoxetine hydrochloride(46), etamsylate (43), ranitidine (52) and aceclo-fenac (35) are examples. Etamsylate is 2,5-di-hydroxybenzene sulfonic acid containing an N-ethylethanamine group. The DSC thermograms
of the mixtures of etamsylate and lactose sho-wed additional peaks, in addition to thoserecorded for the individual components. In thecase of the etamsylate–lactose mixture anadditional prominent endotherm appeared at118.5°C. The main peak at 136.7°C in theoriginal etamsylate thermogram shifted to alower temperature of 131.4°C. This was pro-bably due to solid solubility of lactose inetamsylate (43).
Ranitidine HCl is a drug used for the treatmentof gastric ulcer. The drug is a secondary amine.An incompatibility was reported in a 1:1 binarymixture of the drug and lactose. The DSCthermogram of lactose monohydrate showed adehydration peak at 150°C followed by anendothermic melting peak at 222°C. However,the thermogram of the binary mixture showed abroader peak at 150°C and the disappearanceof the melting peak of lactose at 222°C,indicating a possible interaction betweenranitidine and lactose (52). Aceclofenac is aNon-Steroidal Anti-inflammatory drug(NSAID) with a secondary amine group. Itshowed an incompatibility with spray-driedlactose (SDL). In the binary mixture ofaceclofenac and SDL (7:3), an IR peak at1848.6 cm using pure aceclofenac was-1
observed. This peak disap-peared and anotherpeak at 1771.5 cm shifted to 1762.8 cm . In-1 -1
the mixture of aceclofenac and SDL at a ratioof 6:4, peaks at 1848.6 and 1771.5 cm-1
disappeared completely using pure aceclofenac.A further increase in the SDL concentrationgave similar results (35).
There are also some reports of lactoseinteraction with drugs not having a primary orsecondary amine group such as Fluconazoleand Pefloxacin. The mixture of fluconazole andlactose showed additional peaks by DSC at86.1°C and 136.4°C respectively, in addition tothe peak corresponding to the melting of puredrug at 140.2°C. This indicates an interactionbetween the drug and the excipient (43).
The antibacterial drug pefloxacin mesylate alsodoes not contain a primary or secondary amine
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 9
![Page 8: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/8.jpg)
Review Paper
group but is reported to interact withanhydrous dextrose, Pearlitol® (mannitol),Lactopress SD (directly compressible lactose),Lactochem FP [Natural L (+) Lactic Acid], andLycatab® (starch/calcium carbonate), as indica-ted by the loss of the characteristic meltingendothermic peak of perfloxacin mesylate inthe DSC thermogram. The enthalpy changes inadmixtures were within a 10% limit of thecalculated enthalpy. However, the results ofisothermal stability studies did not support theconclusions from the DSC results (55). Sinceelevated temperatures in DSC study are notnecessarily relevant to ambient conditions,isothermal stress results are more reliable.Further, additional stability studies of prototypeformulation at accelerated conditions can becarried out to discover any potential incom-patibility. Another tertiary amine drug, prome-thazine hydrochloride used as an antiemetic,antihistamine and sedative, resulted in a browncolor in stressed binary mixture studies (storedat 55°C for 3 weeks) indicating a potential in-teraction with lactose monohydrate (45).
Meglumine is an amino sugar derived fromsorbitol. The incompatibility of the antidiabeticdrug glipizide with the blend of meglumine/TRIS buffer has been reported. An interactionwas observed between meglumine and glipizidebut the mechanism has not been established. Ayellow coloration caused by the interaction ofthe amine group of meglumine/TRIS bufferand lactose was observed. Because the solubilitymodifier (meglumine/TRIS buffer) was requi-red to increase the solubility of glipizide in theformulation, the presence of lactose in the for-mulation was considered detrimental to long-term stability. In addition, a melting endo-thermic peak of glipizide was found to be mis-sing in a glipizide–lactose mixture, whichsuggested an interaction between the two com-ponents. A sharp endothermic peak at130.32°C was observed in the DSC thermo-gram of meglumine, which broadened andshifted to lower temperature (122.81°C) for aglipizide and meglumine mixture. The drugpeak was completely absent in the DSC trace of
the mixture, which suggested a possible interac-tion.
The DSC trace of TRIS buffer showed twoendothermic peaks at 139.14ºC (probably dueto evaporation of adsorbed moisture) and172.73°C (melting point of TRIS buffer),followed by an endotherm at 300°C, probablydue to the decomposition of TRIS buffer. Inthe thermogram of glipizide and TRIS buffermixture, the TRIS buffer peak at 139.14°Cshifted to a lower temperature (135.60°C). Inaddition, the drug peak was missing and abroad endothermic peak was observed at296.16°C (56). The DSC results were indicativeof an interaction between glipizide and TRISbuffer. However, the IR spectrum of glipizide–TRIS buffer mixture showed the presence ofcharacteristic bands corresponding to glipizide.There was no appearance of new bands. Hence,there was strong evidence of unchanged drugstructure and lack of chemical interaction bet-ween the two. Thus, it was concluded that therewas no chemical incompatibility between glipi-zide and TRIS buffer. The results confirmed that DSC could be usedas a rapid method to evaluate the compatibilitybetween a drug and excipients. However,caution needs to be exercised while interpretingthe DSC results alone. Wherever possible,results from other techniques such as IR andquantitative analysis after storage under stressedconditions, should be taken in conjunction withDSC results to reach any definite conclusion. Inthe present example, the results from the DSCalong with IR and/or HPLC were successfullyemployed to assess the compatibility of glipizi-de with the excipients used in the developmentof extended release formulations. Based on theresults of IR and/or HPLC analysis, any pos-sible pharmaceutical incompatibility betweenglipizide and TRIS buffer and magnesiumstearate was ruled out. Other APIs which showpossible incompatibilities in binary mixtureswith lactose include ketoprofen (36, 37),picotamide (48), primaquine (44), clenbuterol(50), sennosides A and B (103) and lisinopril(41).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 10
![Page 9: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/9.jpg)
Review Paper
Mannitol is a sugar alcohol derived from asugar by reduction and is a commonly used,non-hygroscopic and chemically stable exci-pient, with good flow properties and highcompressibility. As such, it is suitable for usewith APIs sensitive to water. It is primarily usedas a diluent (10-90%) in tablet formulations.There have, however, been some reports of adverse effects of mannitol on stability ofdrugs. This has been attributed to continuedcrystallization of mannitol from a system that isinitially only partially crystalline. This can resultin an increase in water activity in amorphousregions where the drug is located, withsubsequent adverse effects on stability (104).Mannitol was found to be incompatible withomeprazole (57), primaquine (44) and quinapril(9). Mixing mannitol with either of theomeprazole sodium isomers in their racemicforms led to a decrease in the crystallinity of theresulting mixtures. In the case of S- and R,S-omeprazole sodium the crystallinity is lost.Mixing of mannitol and R-omeprazole sodiumleads to the decrease in melting temperaturesand broadening the melting peaks that can beattributed to the interaction between twodifferent crystalline structures. There was bettercompression of the S-omeprazole–mannitolmixture resulting in a smoother tablet surface,compared to that of R-omeprazole–mannitol.Significant physical interaction of R-omeprazole with mannitol was observed fromlocalized thermal analysis (LTA) and DSCresults (57).
Despite of the well known interaction oflactose with drugs that contain primary andsecondary amine groups, it continues to be oneof the most widely used diluents. Most of theMaillard reactions may be prevented byreducing the water activity in the formulationsand using appropriate packaging. Castello andMattocks (1962) reported that the Maillardreaction occurs only in the presence of anamine base and not in the presence of the salt.The release of free-base from the amine saltoccurs by reaction of the alkaline lubricant, forexample magnesium stearate, which removeshydrogen ion with the formation of stearic acid,furnishing an alkaline medium in the adsorbedmoisture (105).
Stearates
Magnesium stearate is widely used as a lubricantin the manufacture of pharmaceutical soliddosage forms. Literature shows that there arenumerous reports of the incompatibilitybetween stearates and active pharmaceuticalingredients. Chemical incompatibility betweenaspirin and magnesium stearate results in anumber of potentially undesirable products,such as salicylic acid, salicyl salicylic acid andacetyl salicyl salicylic acid (106, 107). Severaltheories have been suggested to explain themechanism of this chemical incompatibility.Acetylsalicylic acid is a moisture-sensitive drug(108) hence its degradation is often associatedwith the presence of water (109) and/oralkaline pH (110). Tablet mixtures containingaspirin and drugs with easily-acetylated groupsreact to give acetyl compounds and salicylicacid. Troup and Mitchner (111) reported thereaction of phenylephrine hydrochloride withacetylsalicylic acid where an acetyl group istransferred from acetylsalicylic acid to thephenylephrine. For example, mixtures ofphenylephrine hydrochloride and aspirincontained 80% of acetylated phenylephrineafter 34 days at 70°C. Adding starch andmagnesium stearate slowed this reaction toabout 1% in 34 days, while adding magnesiumstearate alone resulted in completedecomposition in 16 days. In addition somediacetylated product was produced. Thisreaction may proceed by direct acetylation.Similarly, aspirin tablets containing codeine oracetaminophen yielded acetylated drugs whenheated (112, 113). Kornblum and Zoglio (109)found that the rate of decomposition ofacetylsalicylic acid in suspensions with lubri-cants, such as magnesium stearate, was asso-ciated with the high solubility of the mag-nesium salt of acetylsalicylic acid. This formed abuffer with solvated acetylsalicylic acid, creatinga pH environment that was detrimental to thestability of the compound. It has also beensuggested that the presence of MgO impuritiesin magnesium stearate catalyze degradation bycreating an alkaline pH environment (59).However, the relationship between pH and
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 11
![Page 10: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/10.jpg)
Review Paper
decomposition is controversial, with someauthors claiming that pH does not play asignificant part in the solid state decomposition(106). Other reports suggested that the mainmechanism of incompatibility was a reductionin the melting point of acetylsalicylic acid,which would generate a liquid layer on thesurface of the magnesium stearate particles,thereby accelerating decomposition. Thepresence of liquid films around decomposingacetylsalicylic acid particles was demonstratedby microscopic examination. Similarly, Millerand York (60) described the formation of amagnesium stearate surface film aroundacetylsalicylic acid particles, suggesting that theintimate contact between the two materials mayfacilitate the lowering of the acetylsalicylic acidmelting point (61, 62). Further Gordon et al.(85) noticed that in the presence of stearatesibuprofen forms a eutectic which sublimates.
Oxprenolol hydrochloride, a drug used for thetreatment of angina pectoris showed anincompatibility in a binary mixture withmagnesium stearate. The binary mixtureshowed two overlapping endothermic peakswith onsets of transition at 85°C and 96°C. Thebroad melting endotherm at 110°C to 118°Cfor magnesium stearate was absent in the binarymixture (42). Albendazole, a benzimidazoleclass of anthelmintic drug showed anincompatibility in a 1:1 binary mixture withmagnesium stearate. Exposure of the binarymixture to heat and moisture resulted indegradation confirmed by DSC and HPLC (75). Compatibility studies of the ACE inhibitorfosinopril sodium with different excipients and20% added water resulted in the formation ofdegradation product A as shown in Figure 3.However, in the presence of magnesiumstearate, formation of product A was acce-lerated along with the formation of two otherdegradation products B and C (Figure 3). Thestructure of degradation product C appears tobe incorrectly transcribed in the original paper(additional terminal methyl should not bepresent) (40). Based on an HPLC investigation,90% of the drug degraded in 1 week. In aseparate study, when a 1:1 mixture of fosinopril
sodium and magnesium stearate was exposed to75% RH at 50°C, the degradation of fosinoprilsodium after 3 weeks was less than 1%. Thiswas because both fosinopril sodium andmagnesium stearate were non-hygroscopic,although the interaction between them ismediated by water. This would not be the casein capsules and tablets where other formulationcomponents, such as microcrystalline cellulose,starch, gelatin shell etc., would result inmoisture sorption (40).
The antitumor drug, b-lapachone showed aninteraction with magnesium stearate based onFTIR studies. The disappearance of differentmagnesium stearate bands at 1579.5 and 1465.7cm from the FTIR spectra for both, stressed!1
mixtures (samples were stored in an oven at40ºC and 75% relative humidity in closedcontainers using sodium chloride saturatedsolutions for a month) and thermally stressedmixtures (the drug, some excipients and itsmixtures were subjected to thermal stress byheating up to 160ºC at a rate of 10ºC min )!1
suggested the decomposition of the excipient.Additionally, some changes were observed inthe â-lapachone bands at 2978 cm and!1
1568 cm assigned to the aromatic C-H and C-!1
C respectively. Heating-cooling DSC (HC-DSC) experiments confirmed the hypothesis ofmagnesium stearate degradation since thesecond heating revealed only the melting peakof â-Lapachone, which was observed at a lower
Figure 3 Interaction between Fosinopril sodium and
magensium stearate (40).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 12
![Page 11: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/11.jpg)
Review Paper
temperature and associated enthalpy and noneof the magnesium stearate thermal events wereobserved. Heating to 160°C does not promotechanges in the morphology of â-Lapachone ormagnesium stearate separately but when heatedtogether the sample becomes black as a resultof the degradation of magnesium stearate. Thisevidence of interaction suggests that magne-sium stearate should be avoided in â-lapachoneformulations (76).
Captopril is a pyrrolidine carboxylic acid deriva-tive used in the treatment of hypertension. Itshowed surface interactions with metallicstearates during grinding (5 min at roomtemperature at 32% or 80% RH). A mixture ofcaptopril and each metallic stearate before andafter grinding gave different results in DSC,thermogravimetric (TGA) and FTIR studies.Although there was no interaction betweencaptopril and sodium stearate during grinding,grinding could induce the trans cis iso-merization of captopril in a ground mixture ofcaptopril–sodium stearate. There was noevidence of solid-state interaction betweencaptopril and monoaluminum stearate, butgrinding appeared to accelerate the solid-stateinteraction of captopril with magnesiumstearate. The solid-state interaction betweencaptopril and magnesium stearate wasevidenced by the shifting of the IR spectralpeak for the -COOH of the stearate moietyfrom 1578 cm to 1541 cm . This was due to-1 -1
the interaction of the -OH group in thecarboxylic acid function of captopril withbridging coordination of the –COO group of-
magnesium stearate via hydrogen bondinginvolving water. The interaction betweencaptopril and magnesium stearate was stoppedat 60°C due to evaporation of water from theground mixture (68). Another group of re-searchers (69) also noticed similar type of re-sults for a captopril and magnesium stearatemixture. The DSC thermogram of the binarymixtures indicated a possible interaction due tothe disappearance of the characteristic captoprilfusion peak.
Chlorpropamide, a sulfonylurea antidiabeticdrug showed a possible solid-solid interaction,but not necessarily a pharmaceutical incom-patibility, in a binary mixture of chlorpro-pamide with magnesium stearate. The DSCcurve of the chlorpropamide/magnesium stea-rate mixture resulted in only one endothermicevent at 96.3–108.6°C suggesting a drug–excipient interaction when heated. A substantialdecrease in the dissolution rate was observedfor chlorpropamide tablets containing magne-sium stearate after 6 months of storage at40°C/75% RH (65). The ACE inhibitorquinapril, a tetrahydroisoquinoline carboxylicacid, was incompatible with magnesium stearatedue to the basicity of magnesium stearate, andbecause the rate of degradation was mediatedby the availability of moisture (9). DSC studiesshowed that the antiviral drug, acyclovir alsointeracted with magnesium stearate, as shownby the disappearance of the characteristic acyc-lovir fusion peak in the thermogram of thebinary mixture. X-ray powder diffraction(XRPD) did not provide evidence of anincompatibility between acyclovir and magne-sium stearate, since the diffraction peaks remai-ned unaltered in the physical mixture. The maindifference observed in the FTIR of binarymixtures of acyclovir and stearic acid was thesignificant decrease in the band attributed tothe -OH group, indicating a possible chemicalinteraction between these compounds (58).
The sedative drug, doxylamine succinate, wasincompatible with magnesium stearate, stearicacid, povidone (PVP) and lactose (53). Saltforms of cysteine showed interaction withmagnesium stearate and other excipients suchas xylitol, sorbitol and two gum bases, Every TToco and Smily 2 Toco (114). Other APIswhich have been found to be incompatible withstearates are glimepiride (66), cephalexin (71),glipizide (56), ibuproxam (8), indomethacin (63,64), ketoprofen (38), moexipril (10, 30, 70),nalidixic acid (73), primaquine (44), promet-hazine hydrochloride (45), temazepam (42),glibenclamide (67), penicillin G (74), oxacillin(74), clopidogrel besylate (77) and erythromycin(72). It has been suggested that stearate salts
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 13
![Page 12: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/12.jpg)
Review Paper
should be avoided as tablet lubricants if theAPI is subject to ion-catalyzed degradation.The degradative effect of alkali stearates isinhibited in the presence of malic, hexamic andmaleic acid due to competition for the lubricantcation between the drug and additive acid (115).In some cases the interactions may not occur atthe typical use level of magnesium stearate(0.25% to 0.5%). An even more importantconcern is mixing time, which can directlyaffect the disintegration time and dissolution ofthe drug from the solid dosage form. This is adetrimental physical interaction.
Povidone (PVP, polyvinyl pyrrolidone,copovidone)
PVP is commonly used as a binder in tabletformulations, as a film forming agent, and alsofor forming amorphous dispersions of drugs. Itwas found to be incompatibile with a widerange of APIs. The antimicrobial drug sulfat-hiazole interacted with PVP, the rate increasingat higher PVP concentrations (78). In the DSCthermogram of an oxprenolol:PVP mixture,apart from the adsorbed water endotherm, asecond broad endotherm, followed bydegradation and/or vaporization was seen,while the endotherm characteristic of oxpreno-lol hydrochloride was absent indicating aninteraction (42). Evidence of an interactionbetween the antihypertensive drug atenolol andPVP showed substantial changes in the DSCthermograms of a drug-excipient binary mix-ture. This interaction was enhanced ormediated by the free (unbound) water of thePVP. Indications of interaction were greater inthe PVP-rich mixture, in the moisture treatedmixtures, and in mixtures annealed (at 70°C) inclosed containers, where relative humiditywould be expected to be higher than in opencontainers. Temperature conditioning onlyaffected (on the atenolol melting enthalpy)considerably after prolonged annealing in aclosed container. This effect was less than thatcaused by moisture conditioning which, inaddition, also appeared to modify the crystallineorder of the atenolol (63).
A strong interaction between PVP and halo-peridol was observed, favored by mechanicalstress and more evident in the 20:80 binarymixture. The melting peak of the haloperidolshowed a low temperature shoulder. The onsettemperature of this shoulder corresponded tothat of the peak present in the 20:80 mixture.The total enthalpy change was about 18%lower than would have been expected if nointeraction had occurred between thecomponents (79). PVP also showed aninteraction with ibuproxam (8), indomethacin(63, 64), ketoprofen (36-38), clenbuterol (50)and temazepam (42). At 2% to 5% PVP maynot prove detrimental to many drugs. However,when used at higher levels for specializedapplications such for the formation of amorp-hous dispersions, then the interactions may bedeleterious. Since PVP is produced by freeradical polymerization of N-vinylpyrrolidoneusing hydrogen peroxide as an initiator; acommercial PVP always contain traces ofunreacted peroxides which may oxidize APIs.Therefore for drugs where peroxide degra-dation may be of concern (e.g. Ranitidine HCl),the use of PVP as a binder should be avoided.Hartauer et al. (25) reported that the presenceof povidone and crospovidone, in the tabletformulation of raloxifene hydrochloride, led tooxidation of the drug. The formation of the N-oxide derivative of the drug substance wasconfirmed based upon spectroscopic charac-terization and chromatographic comparison tothe synthetic N-oxide. However, the dissolutionof Raloxifene HCl could not be achievedwithout using PVP (116). Same authors alsoshowed that phenolic impurities in tabletbinding agents, such as povidone and disin-tegrants such as crospovidone, can lead tophotodegradation of the drug through freeradical reactions.
Dicalcium phosphate dihydrate (DCPD,Emcompress )®
DCPD is commonly used a filler in tabletformulations and as a dental polishing agent intoothpaste that contains sodium monofluoro-phosphate. It is one of the most common
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 14
![Page 13: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/13.jpg)
Review Paper
diluents for tablets, but is susceptible todehydration at quite low temperatures in thepresence of water vapor, thus crucial choosingconditions for processing and storage of thedosage forms. It has been shown to beincompatible with a number of acidic drugs aswell as with sodium salts of poorly watersoluble drugs due to its alkaline nature (117,118).
Temazepam is a benzodiazepine hypnotic drug.It is acidic in nature with pKa of 1.61 andtherefore when formulated with the basicexcipient DCPD, an interaction was observedas indicated by DSC results (42). Thecombination of the antihypertensive drugoxprenolol hydro-chloride with DCPD showed,apart from the characteristic oxprenololhydrochloride endo-therm, an extra endodermwith an onset of 136°C indicating an interaction(42). The ACE inhibitor ceronapril, which isincompatible with lactose, was also found to beincompatible with DCPD. HPLC studies ofmixtures of ceronapril with DCPD showed thatceronapril degraded by 2.5% after 3 weeks ofstorage. The degradation product formed inpresence of DCPD was identified (Figure 4)using LC-MS and liquid chromatographycoupled with mass spectrometry/massspectrometry (LC-MS-MS). This product wasformed through an oxidative process which wasnot predicted based on initial preformulationtesting (40).
The antitumor drug, â-lapachone is sensitive toalkaline pH and when formulated with DCPDwas found to be incompatible. The heating–cooling DSC results suggested that lapachonepromotes DCPD dehydration at lower tem-peratures, at the same temperature as themelting range of the drug. The DCPD water ofcrystallization (20.9% of the DCPD weight)partially dissolves the â-lapachone and the re-sultant basic environment could decompose theâ-lapachone. This was verified by the secondheating which showed the broad drug meltingpeak shifting to a lower temperature with aslight associated enthalpy change, thus a pos-
sible sign of drug degradation. Accentuatedchanges were also detected in the bandscorresponding to the functional groups of thedrug, in the thermally stressed mixtures (TSM),which indicated chemical decomposition of â-Lapachone (76).
Parthenolide, a naturally occurring furanone,was found to be incompatible with DCPD.This could be attributed to the alkaline natureof DCPD (81). Other drugs which were foundto be incompatible with DCPD include famoti-dine (82), nalidixic acid (73), quinapril (9) andmetronidazole (80).
Eudragit polymers®
Eudragit polymers are copolymers derivedfrom esters of acrylic and methacrylic acid. Thephysicochemical properties of the differentpolymers are determined by the types offunctional groups. These polymers are availablein a range of different physical forms (aqueousdispersion, organic solution granules andpowders) and are widely used for targeted andcontrolled drug delivery. The acidic nature ofsome Eugradit polymers has resulted in anumber of incompatibilities with active ingre-dients.Three NSAIDs, diflunisal, flurbiprofen, andpiroxicam showed interaction with Eudragitpolymers (RS100 and RL100). These re-searchers showed that, due to the acidic natureof Eudragit RS100 and RL100, except formechanical dispersion, the drugs interactedwith Eudragit matrixes by virtue of electrostaticinteractions with the ammonium groups pre-sent in the polymer. These interactions werestronger for drugs bearing a carboxylic moiety,
a thus having lower pK values which signi-
Figure 4 Interaction between Ceronapril with
dicalcium phospate (40).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 15
![Page 14: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/14.jpg)
Review Paper
ficantly affected the drug release profile fromsolid dispersions. The progressive disap-pearance of FT-IR, X-ray, and thermotropicdrug signals in solid dispersion was more likelyrelated to the increasing amount of thepolymers, which exert a diluting effect on drugsignals. DSC of flurbiprofen exhibited a sharpendothermic peak around 115°C, corres-ponding to its melting point. The dispersion offlurbiprofen in the Eudragit RS and, most oftenin the Eudragit RL matrix, at both 1:2 and 1:5weight ratios resulted in a complete suppressionof the drug fusion peak, suggesting a homo-geneous solution of the drug in the polymer.However, the mere physical dispersion of thedrug with Eudragit RS or Eudragit RL alsoresulted in a modification of the thermotropicprofile. At the lower flurbiprofen-polymer ratioa downward shift of the drug fusion peakoccurred in 2 partially superimposed peaks(centered at 98°C and 106°C, respectively). Inthe 1:5 w/w mixture, these peaks were furtherreduced or even absent, giving a DSCthermogram comparable to that of thecorresponding solid dispersion. An XRPDanalysis showed clearly that the systems pre-pared using lower amounts of polymer stillshowed the typical signals for drug crystals.However, increasing the Eudragit RS ratioprogressively weakened their intensity (83, 84).
Ibuprofen (a NSAID) was also incompatiblewith Eudragit. Physical and chemical inte-raction with the carboxylic group of ibuprofenoccurs because of electrostatic interactionsand/or hydrogen bonding with the quaternaryammonium groups in Eudragit RL. Thisprobably inhibits its uniform dispersion in thepolymer network and ultimately affects the drugloading and ibuprofen release profile in vitro andin vivo. Pignatello et al. (86) mixed differentchemical forms of ibuprofen (free acid, sodiumsalt, and n-butyl ester) with Eudragit RL100 atincreasing weight ratios in order to investigatethe role of the carboxylic group in the interac-tion with the Eudragit RL polymer. As the acidform, ibuprofen crystallized within the polymernetwork under the experimental conditionswhen its concentration exceeded the solubility
of the drug in the polymer itself. At lowerweight ratios, the drug existed in an amorphousor microcrystalline state, however, thoroughlydispersed in the polymer matrix. The thermalbehavior of the solid dispersions and mixturessuggested that the polymer inhibited themelting of the drug crystals. A largeendothermic peak is only visible above 140°C,probably due to the beginning of polymerdegradation. The systems containing higherpolymer ratios (33% of Eudragit RL with acid-free form of the drug (IBU/A) and 33% ofEudragit RL with ibuprofen sodium salt(IBU/S) aqueous solution) showed a meltingpeak at 146°C and 97.5°C, respectively. Thesefindings from powder X ray diffraction(PXRD) analysis confirmed that, above acertain concentration, the excess of drug wasnot able to form a homogeneous solid solutionwith the polymer. IR studies showed that,ibuprofen exhibited a strong peak at 1720 cm-1
for carbonyl group stretching, while for its soliddispersion a broader and weaker signal wasvisible, at around 1725 cm (86).-1
A mild interaction between the antiulcer drugranitidine and Eudragit E100 has beenreported. Although there was no alteration inthe DSC thermogram of the ranitidine-Eudragitmixture, compared to those of pure compound,careful examination of DRIFTS spectrum(diffuse reflectance infrared Fourier transformspectroscopy) of 1:1 drug-Eudragit E100mixture revealed a slight shift to a higher wavenumber of the band associated with the
3protonated tertiary amine group R -NH of+
ranitidine HCl at 2560 cm . This suggested a-1
mild interaction, such as hydrogen bonding,between protonated tertiary amine group of thedrug and a functional group on the polymer(52). The use of acidic film formers Eudragit L100, hypromellose acetate succinate(HPMCAS-HF), Hypromellose phthalate grade55 (HP-55), and shellac resulted in instability ofthe acid-labile proton pump inhibitoromeprazole in solid drug-polymer blends ataccelerated storage conditions (40ºC/75% RH).HP-55 caused the highest degree of omeprazoledegra-dation, followed by shellac, HPMCAS-
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 16
![Page 15: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/15.jpg)
Review Paper
HF, and then Eudragit1 L 100 (119). Despite ofthe interaction of methacrylic acid co-polymerswith most drugs belonging to the proton pumpinhibitors group, the polymers are widely usedin enteric coat formulations because of theirability to control drug release within a narrowpH range. The incompatibility is avoided bysuitably protecting the drug using a barriercoating.
Celluloses
Methylcellulose is widely used in a variety oforal and topical pharmaceutical formulations. Itis also extensively used in cosmetics and foodproducts. MCC is used as an inactive filler intablets and as a thickener and stabilizers in pro-cessed foods. Hydroxypropyl methylcellulose(hypromellose) has been used as an excipient inoral tablet and capsule formulations, where,depending on the grade, it functions as acontrolled release agent delaying the release of amedicinal compound into the digestive tract.Different grades can also be used as binders oras a component of tablet coatings
It has been reported that the degradation rateof enalapril maleate was accelerated by severalorders of magnitude in the presence of MCC.The MCC appeared to reduce the apparent heatof fusion of the enalapril maleate. At a heatingrate of 10°C/min, the DSC thermogram forenalapril maleate showed two partiallysuperimposed endothermic events. The firstwas due to melting and the second due tothermal decomposition. This indicated thatdecomposition takes place, to some extent, during melting. Moreover, in the DSCthermogram for the enalapril maleate:MCCbinary mixture, there is an increase in thedegree of overlap of the two events. However,the authors did not attempt to separate thethermal events by decreasing the heating rate(87). Other researchers (88) have also de-monstrated an increase in the degradation rateof enalapril maleate in presence of MCC usingDTA (differential thermal analysis) studies andaccelerated stability testing. Apart from MCC,magnesium stearate, calcium phosphates and
several other common disintegrants (starch,sodium starch glycolate, crospovidone andcroscarmellose sodium) were also shown tocontribute to the decomposition of enalaprilmaleate (120).
Isosorbide mononitrate, a nitrooxy dioxa-bicyclic compound used for treatment of an-gina pectoris showed an interaction withcellulose acetate and MCC as evidenced byDSC, IST and HPLC studies. There was also adrastic reduction in the enthalpy value (from125.32 to 34.10 J/g), which also suggested anincompatibility. When IST samples of an iso-sorbide mononitrate:cellulose acetate mixturewere observed after 3 weeks of storage understressed conditions, a yellow coloration wasobserved. The presence of a new peak in theHPLC chromatogram of the stressed samplesof isosorbide mononitrate:cellulose acetate mix-ture further suggested a chemical interaction(6).
HPMCAS is a widely used excipient in soliddispersion technology. HPMCAS potentiallyundergoes hydrolysis to produce succinic acidand acetic acid, the hydrolysis rate being higherat higher temperatures and higher relativehumidities. The use of HPMCAS is notrecommended for APIs containing hydroxylgroup(s) due to the potential of ester formationwith succinic acid and/or acetic acid. Dyphyl-line, a drug used to treat bronchial asthma,consists of a purine skeleton with a 2,3-dihydroxy-side chain. In order to test thepotential incompatibility of hydroxy groupcontaining APIs with HPMCAS, Dong andChoi (89) used a dyphylline as a model drug.Dyphylline was stored at 140°C for 5 hours inthe following three forms: (a) pure powder, (b)physical mixture with succinic acid (50:50) and© physical mixture with HPMCAS with adrug–excipient ratio of 40:60 to mimic a 40%loading HME (hot melt extrusion) compo-sition. The samples were dissolved in a diluent(95% pH 8.25 50 mM phosphate buffer + 5%acetonitrile) to form a 0.1 mg/mL solution ofdyphylline for HPLC analysis. Upon heattreatment, three degradants were observed in
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 17
![Page 16: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/16.jpg)
Review Paper
the physical mixture of dyphylline andHPMCAS. They were identified as two mono-esters and one di-ester of two dyphyllinemolecules with one succinic acid molecule(Figure 5), suggesting potential drug–excipientincompatibility during formulation develop-ment (89).
The diuretic drug, trichlormethiazide was foundto be stable in a solid state under humid con-ditions, but when made into tablets was notstable under the same conditions. Trichlor-methiazide degradation was accelerated by theaddition of hydroxypropylcellulose. Variousfactors that could affect the trichlormethiazidestability in tablets were considered, such as,adsorption of water, amount of free water andpH (90).
Polyethylene glycol (PEG)
PEG is widely used as a lubricant and as acosolvent/dispersant for poorly soluble drugsin pharmaceutical dosage forms. The purity ofPEG plays a very important role in thedegradation of drugs. High purity gradesavailable from reputable manufacturers are lesslikely to lead to degradation of drugs.Ibuprofen showed an incompatibility with PEGin tablets stored for three weeks at 70°C/75%RH resulting in the formation of ibuprofendegradation products. One of the identified de-
gradation products was a known toxin 4-isobutylacetophenone (91). Aspirin undergoespseudo-first order decomposition in com-bination with several grades of PEGs due inpart to trans-esterification to form salicyclicacid and acetylated PEG (121). The rate ofdecomposition was considerably greater when afatty base, such as cocoa butter, was used (122).Analysis of commercial batches of 100 mgindomethacin-PEG suppositories showed thatapproximately 2%, 3.5% and 4.5% of the origi-nal amount of indomethacin was esterified withPEG 300 after storage of one, two and threeyears respectively. The formation of poly-ethylene glycol (PEG) sulfonate/ besylate estershave been reported during hot melt granulationof clopidogrel besylate with PEG 6000, severalof which are genotoxic (77). Other APIs whichshowed interaction with PEG are ibuproxam(8) ketoprofen (38) and calcium phosphomycin(92).
Polysorbate 80
Polysorbate 80, commercially known asTween 80, is a nonionic surfactant and®
emulsifier used in food and pharmaceuticals.Formation of peroxide in neat polysorbate 80in the presence of air during incubation atelevated temperatures has been reported. Thiscan affect the stability of oxidation-sensitivedrugs (123). Ibuprofen showed an incom-patibility with polysorbate 80 in tablets storedfor three weeks at 70°C/75% RH (91).
Sodium lauryl sulfate (SLS)
SLS is widely used in solid oral formulations asa surfactant/wetting agent to improve the solu-bility of poorly soluble drugs. Incompatibilitybetween the antidiabetic drug chlorpropamideand SLS has been reported. The DSCthermogram of a chlorpropamide/SLS mixtureshowed a wide endotherm at 99-120°C with thedisappearance of the double melting peak ofthe drug. A considerable decrease in thedissolution rate of chlorpropamide from tabletscontaining SLS was observed after 6 months of Figure 5 Interaction between hydroxypropyl
methylcellulose acetate succinate and dyphylline (89).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 18
![Page 17: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/17.jpg)
Review Paper
storage at 40°C/75% RH which clearlysuggested incompatibility between the activedrug and excipient. (65). An in vitro study foundthat chlordiazepoxide, which can exist incationic form, formed an ion pair with theanionic SLS, resulting in decreased membranepermeability (11, 93). The anti-coagulant drug,clopidogrel besylate was also found to beincompatible with SLS (77).
Chitosan
Chitosan has been investigated as an excipientfor use in direct tablet compression, as a tabletdisintegrant, for the production of controlledrelease solid dosage forms and for theimprovement of drug dissolution (124).Chitosan inhibited the release of the NSAIDdiclofenac sodium from matrix tablets at lowpH, possibly due to the formation of an ioniccomplex between the diclofenac sodium andthe ionized amino groups of the cationicpolymer (11, 94). Chitosan also interacted withpiroxicam. The solubility of piroxicam and it’sbiological availability increased 10-fold whenmixed with chitosan (95).
Magnesium oxide
Magnesium oxide is used in antacids as anactive ingredient and may also be used as a pHmodifier (e.g. in Levothyroxine sodium penta-hydrate tablets) (125). A solid–solid reaction in1:1 and 2:1 mixtures of ibuprofen/magnesiumoxide stored at 55°C has been reported asshowed by the disappearance of ibuprofen mel-ting endotherm in DSC curve and changes inthe infrared spectrum after reaction.Comparison with authentic samples indicatedthat Mg(diibuprofen) was the product of thereaction (Figure 6). This reaction is greatlyinfluenced by moisture and the molecularmobility of the reactants. Solid–solid reactionsof ibuprofen were also observed with basicoxides (e.g. calcium oxide) and hydroxides (e.g.magnesium hydroxide) (96).
Silicon dioxide (Silica)
2In pharmaceuticals, silica (SiO ) is used as aglidant during tablet manufacturing. Colloidal
2 SiO was found to noticeably decrease thethermal stability of enalapril maleate. TheTG/DTG and DSC thermograms of the binary
2mixtures of enalapril maleate and SiO
2indicated that SiO results in a decrease of morethan 20°C in the onset temperature ofdegradation of the drug. Therefore, the use of
2SiO as an excipient should be avoided informulations containing enalapril maleate, sinceit may act as a catalyst in the thermal
2decomposition of the drug even though SiO isusually employed at low concentrations(typically <1% mass/mass) (120).
Carbonates
The addition of aqueous soluble carbonatesalts, such as sodium carbonate, compromisedthe stability of adefovir dipivoxil in the solidstate, increasing the hydrolysis of the drug(Figure 7). However, aqueous insoluble car-bonates, such as calcium carbonate and mag-nesium carbonate, enhanced the stability ofadefovir dipivoxil as compared to a controlformulation. Pivalic acid, a degradation productof adefovir dipivoxil, was shown to acceleratethe degradation rate of adefovir dipivoxil in thesolid state. The de-stabilizing effect of this acidon adefovir dipivoxil stability was diminished inthe presence of magnesium carbonate. Pivalicacid also increased the rate at which adefovirdipivoxil dimers were formed in the presenceof formaldehyde vapor. Addition of insolublecarbonates reduced the rate of formaldehyde-catalyzed dimerization of adefovir dipivoxil(97). Solid–solid reactions of ibuprofen with so-dium bicarbonate and potassium carbonatewere also observed (96).
Figure 6 Acid-base reaction of ibuprofen and
magnesium oxide (96).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 19
![Page 18: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/18.jpg)
Review Paper
Miscellaneous
Apart from API-excipient incompatibilitiesdiscussed above, several other incompatibilitieshave been reported as summarized in Table 3.
Table 3. Miscellaneous API-excipient incompatibilities
Excipient (s) API Reference
Ascorbic acid, citric acid, butylatedhydroxyanisole
Atenolol (126)a
Maize starch, pregelatinized starch,sodium starch glycolate, Avicel PH 101
® Clenbuterol (50)
Plasdone Glimepiride (66)®
Palmitic acid Ketoprofen (38)
Methyl paraben, cetostearyl alcohol,glyceryl monostearate
Lapachol (127)
Methyl paraben, propyl paraben, butylatedhydroxytoluene, acetylated lanolin
Lipoic acid (128)
2Succinic Acid Na –Phosphomycin (92)
Sodium dioctylsulfosuccinate Ca–Phosphomycin (92)
Pearlitol SD200® c Promethazine
hydrochloride(45)
Precirol ATO 5 Temazepam (42)® d
Ca and Mg salts Tetracycline (98)
Sodium edetate, sodium bisulfite Hydralazine HCl (129)e
Talc Saproxetine maleate (47)f
Vitamin E succinate-processed films Tetrahydrocannabinol (130)
Formation of the degradation products (N-formyl atenolol, carbamic formic anhydridea
of atenolol, –acetyl atenolol) have been reported
Incompatibility was indicated by yellow to brown coloration or white precipitationb
Pearlitol SD is a spray dried mannitol containing 20% maize starchc
Precirol Ato 5 is a glyceryl palmitostearate and is used as multipurpose functionald
excipient (lubricant, sustained release agent and/or a taste masking agent for oral dosageforms
A yellow coloration was observede
The amide derivative was formed due to interaction of drug with maleic acid in thef
presence of talc
CONCLUSION
Drug-excipient interactions/incompatibilitiesare major concerns in formulation deve-lopment. Selection of the proper excipient du-ring preformulation studies is of prime impor-tance. Acid-base interactions and Maillardreactions are probably the most common API-excipient interactions reported. The excipientslactose and magnesium stearate are the mostwidely used excipients in oral solid dosageforms. Combined with their propensity forreaction with certain functional groups, it is noaccident therefore, that they are involved inhigher number of incompatibilities and shouldalways be used with caution. Use of lactose as a
diluent should be avoided for activepharmaceutical ingredients containing aminesdue to the possibility of a Maillard reaction.Stearate salts should be avoided as tabletlubricants if the API is subject to hydrolyticion-catalyzed degradation. Alkaline excipientssuch as DCPD should not be used in theformulation of acidic drugs. The use ofEudragit RL should be avoided with drugscontaining a carboxyl group (e.g. ibuprofen, lo-wer pKa) since these exhibit strong electrostaticinteraction with ammonium groups present inEudragit polymer affecting the release profileof the active ingredient. Care should also betaken when formulating drugs containinghydroxyl groups. The use of HPMCAS shouldbe avoided due to potential ester formationwith succinic acid or acetic acid. Although, inmany of the examples discussed above, theincompatibility is evident at elevated tempe-ratures or at unrealistically high concentrationratios of excipient to API, and thus they maynot be seen at ambient (real) temperatures or atcommonly used excipient to API ratios for theduration of the product shelf-life. However,such information is very helpful for analyzingany instability issues with commercial for-mulations or during the development of newformulations. Once solid-state reactions areunderstood in a pharmaceutical system, thenecessary steps can be taken to avoid thereactivity and improve the storage stability fordrug products.
REFERENCES
1 Rowe RC; Sheskey PJ; Quinn ME, Handbook ofPharmaceutical Excipients. 6th Edition ed.;Pharmaceutical Press: London, 2009.
Figure 7 Hydrolysis of adefovir dipivoxil (97).
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 20
![Page 19: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/19.jpg)
Review Paper
2 Clas SD; Dalton CR; Hancock BC, Differentialscanning calorimetry: applications in drugdevelopment. Pharm. Sci. Technol. Today 2, 311-320, 1999.
3 Giron D, Contribution of thermal methods andrelated techniques to the rational development ofpharmaceuticals—Part 2. Pharm. Sci. Technol.Today 1, 262–268, 1998.
4 Sims JL; Carreira JA; Carrier DJ; Crabtree SR;Easton L; Hancock SA; Simcox CE, A Newapproach to accelerated drug-excipient compatibilitytesting. Pharm. Dev. Technol. 8, 119-126, 2003.
5 Vueba ML; Veiga F; Sousa JJ; Pina ME,Compatibility studies between ibuprofen orketoprofen with cellulose ether polymer mixturesusing thermal analysis. Drug Dev. Ind. Pharm.31, 943-949, 2005.
6 Verma RK; Garg S, Compatibility studies betweenisosorbide mononitrate and selected excipients usedin the development of extended re leaseformulations. J. Pharm. Biomed. Anal. 35, 449-458,2004.
7 Phipps MA; Mackin LA, Application of isothermalmicrocalorimetry in solid state drug development.Pharm. Sci. Technol. Today 3, 9-17, 2000.
8 Mura P; Faucci MT; Manderioli A; Bramanti G;Ceccarelli L , Compatibility study betweenibuproxam and pharmaceutical excipients usingd ifferentia l scanning calorimetry, hot-stagemicroscopy and scanning electron microscopy. J.Pharm. Biomed. Anal. 18, (151-163), 1998.
9 Thomas VH; Naath M, Design and utilization of thedrug–excipient chemical compatibility automatedsystem. Int. J. Pharm. 359, 150–157, 2008.
10 Byrn SR; Xu W; Newman AW, Chemical reactivityin so lid -sta te pharmaceuticals: form ulationimplications. Adv. Drug Del. Rev. 48, 115–136,2001.
11 Jackson K; Young D; Pant S, Drug–excipientinteractions and their affect on absorption. PSTT 3,(10), 336-345, 2000.
12 Monkhouse DC; Maderich A, Whither compatibilitytesting? Drug Dev. Ind. Pharm. 15, 2115-2130,1989.
13 Crowley PJ, Excipients as stabilizers. Pharm. Sci.Technol. Today 2, 237-243, 1999.
14 Maulding HV; Zoglio MA; Pigois FE; Wagner M,Pharmaceutical heterogeneous systems IV: A kineticapproach to the stability screening of solid dosageforms containing aspirin. J. Pharm. Sci. 58, 1359-1362, 1969.
15 Kontny MJ; Grandolfi GP; Zografi G, Water vaporsorption of water-soluble substances: studies ofcrystalline solids below their critical relativehumidities. Pharm. Res. 4, 104-112, 1987.
16 Callahan JC; Cleary GW; Elefant M; Kaplan G;Kensler T; Nash RA, Equilibrium moisture contentof pharmaceutical excipients. Drug Dev. Ind.Pharm. 8, 355, 1982.
17 Hancock BC; Shamblin SL, Water vapor sorption bypharmaceutical sugars. Pharm. Sci. Technol. Today1, 345–351, 1998.
18 Kontny MJ, Distribution of water in solidpharmaceutical systems. Drug Dev. Ind. Pharm. 14,1991-2027, 1988.
19 Genton D; Kesselring UW, Effect of temperatureand relative humidity on nitrazepam stability in solidstate. J. Pharm. Sci. 66, 676-680, 1977.
20 Chemburkar PB; Smyth RD; Buehler JD; Shah PB;Joslin RS; Polk A; Reavey-Cantwell NH, Correlationbetween dissolution characteristics and absorptionof methaqualone from solid dosage forms. J. Pharm.Sci. 65, 529-533, 1976.
21 Horhota ST; Burgio J; Lonski L; Rhodes CT, Effectof storage at specified temperature and humidity onproperties of three directly compressible tabletformulations. J. Pharm. Sci. 65, 1746-1749, 1976.
22 Byrn SR; Kessler DW, The solid-state reactivity ofthe crystal forms hydrocortizone esters. Tetrahedron43, 1335 -1343, 1987.
23 Byrn SR; Lin CT, The effect of crystal packing anddefects on desolvation of hydrate crystals of caffeineand L-(2)-1,4-cyclohexadiene-1-alanine. J. Am.Chem. Soc. 98, 4004–4005, 1976.
24 Byrn SR; Sutton PA; Tobias B; Frye J; Main P,Crystal structure, solid-state NMR spectra, andoxygen reactivity of five crystal forms ofprednisolone tertbutylacetate. J. Am. Chem. Soc.110, 1609–1614, 1988.
25 Hartauer KJ; Arbuthnot GN; Baertschi SW;Johnson RA; Luke WD; Pearson NG; Rickard EC;Tingle CA; Tsang PKS; Wiens RE, Influence ofperoxide impurities in povidone and crospovidoneon the stability of raloxifene hydrochloride intablets: identification and control of an oxidativedegradation product. Pharm. Dev. Technol. 5,303–310, 2000.
26 Maillard LC, Action of amino acids on sugars.Formation of melanoidins in a methodical way.Comp. Rend. 154, 66-68, 1912.
27 Buxton PC; Jahnke R; Keady S, Degradation ofglucose in the presence of electrolytes during heatsterilization. Eur. J. Pharm. Biopharm. 40, 172-175,1994.
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 21
![Page 20: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/20.jpg)
Review Paper
28 Monkhouse DC, Excipient compatibility possibilitiesand limitations in stability prediction. In Stabilitytesting in the EC, Japan and the USA. Scientific andregulatory requirements, Crim W; Krummen K, Eds.Wissenschaftlidie Verlassgellschaft mbH: Stuttgart,1993; pp 67-74.
29 Monajjemzadeh F; Hassanzadeh D; Valizadeh H;Siahi-Shadbad MR; Mojarrad JS; Robertson TA;Roberts MS, Compatibility studies of acyclovir andlactose in physical mixtures and commercial tablets.Eur. J. Pharm. Biopharm. 73, (3), 404-413, 2009.
30 Gu L; Strickley RG; Chi LH; Chowhan ZT, Drug-excipient incompatibility studies of the dipeptideangiotensin-converting enzyme inhibitor, moexiprilhydrochloride: dry powder vs wet granulation.Pharm. Res. 7, (4), 379-83, 1990.
31 Ozdemir FA; Anilanmert B; Pekin M,Spectrophotometric investigation of the chemicalcompatibility of the anticancer drugs irinotecan-HCland epirubicin-HCl in the same infusion solution.Cancer Chemother. Pharmacol. 56, 529–534, 2005.
32 Tong WQ; Zhang GGZ, Stability and excipientcompatibility studies. Integrated Drug ProductDevelopment Process (3 day-course), University ofUtahhttp://www.pharmacy.utah.edu/pharmaceutics/pdf/Stability.pdf, 2006.
33 Connors KA; Amidon GL; Stella VJ, ChemicalStability of Pharmaceuticals: A Handbook forPharmacists. In 2nd ed.; John Wiley and Sons: NewYork, 1986; pp 93-94.
34 Waternnan KC; Adami RC; Alsante KM; Hong J;Landis MS; Lombardo F; Roberts CJ, Stabilizationof pharmaceuticals to oxidative degradation. Pharm.Dev. Technol. 7, 1-32, 2002.
35 Mutalik S; Naha A; Usha AN; Ranjith AK;Musmade P; Manoj K; Anju P; Prasanna S,Preparation, in vitro, preclinical and clinicalevaluations of once daily sustained release tablets ofAceclofenac. Arch. Pharm. Res. 30, (2), 222-234,2007.
36 deCarvalho LAEB; Marques MPM; Tomkinson J,Drug–excipient interactions in Ketoprofen: Avibrational spectroscopy study. Biopolymers 82, 420-424, 2006.
37 de Carvalho LAEB; Marques MPM; Tomkinson J,Drug-excipient interactions in ketoprofen: Avibrational spectroscopy study. Biopolymers 82, (4),420-424, 2006.
38 Mura P; Manderioli A; Bramanti G; Furlanetto S;Pinzauti S, Utilization of differential scanningcalorimetry as a screening technique to determinethe compatibility of ketoprofen with excipients. Int.J. Pharm. 119, 71-79, 1995.
39 Abdoh A; Al-Omari MM; Badwan AA; Jaber AMY,Amlodipine besylate-excipients interaction in soliddosage form. Pharm. Dev. Technol. 9, 15-24, 2004.
40 Serajuddin ATM; Thakur AB; Ghosal RN; FakesMG; Ranadive SA; Morris KR; Varia SA, Selectionof solid dosage form composition through drug-excipient compatibility testing. J. Pharm. Sci. 88,696-704, 1999.
41 Eyjolfsson R, Lisinopril-lactose incompatibility.Drug Dev. Ind. Pharm. 24, 797-798, 1998.
42 Botha SA; Lotter AP, Compatibility study betweenoxprenolol hydrochloride, temazepam and tabletexcipients using differntial scanning calorimetry.Drug Dev. Ind. Pharm. 16, 331-345, 1990.
43 Desai SR; Shaikh MM; Dharwadkar SR,Preformulation compatibility studies of etamsylateand fluconazole drugs with lacose by DSC. J.Therm. Anal. Cal. 71, 651-658, 2003.
44 Bertol CD; Cruz AP; Stulzer HK; Murakami FS;Silva MAS, Thermal decomposition kinetics andcompatibility studies of primaquine under isothermaland non-isothermal conditions. J. Therm. Anal.Calorim., 102, 187-192, 2010.
45 Thumma S; Repka MA, Compatibility studies ofpromethazine hydrochloride with tablet excipientsby means of thermal and non-thermal methods.Pharmazie 64, 183-189, 2009.
46 Wirth DD; Baertschi SW; Johnson RA; Maple SR;Miller MS; Hallenbeck DK; Gregg SM, MaillardReaction of lactose and fluoxetine hydrochloride, asecondary amine. J. Pharm. Sci. 87, 31–39, 1998.
47 Schildcrout SA; Risley DS; Kleemann RL, Drug-excipient interactions of Seproxetine Maleatehemihydrate: Isothermal stress methods. Drug Dev.Ind. Pharm. 19, 1113-1130, 1993.
48 Mura P; Faucci MT; Manderioli A; Furlanetto S;Pinzauti S, Thermal analysis as a screening techniquein preformulation studies of picotamide soliddosage forms. Drug Dev. Ind. Pharm. 24, 747-756,1998.
49 Riaz M; Ami KH, Stability of aminophylline. Pak. J.Pharm. Sci. 6, 35-44, 1993.
50 Signoretti EC; Dell'utri A; Salvo AD; Donini L,Compatibility study between clenbuterol and tabletexcipients using differential scanning calorimetry.Drug Dev. Ind. Pharm. 12, 603-620, 1986.
51 Monajjemzadeh F; Hassanzadeh D; Valizadeh H;Shadbad MRS; Mojarrad JS; Robertson T; RobertsMS, Assessment of feasibility of Maillard reactionbetween Baclofen and lac tose by l iqu idchromatography and tandem mass spectrometry,application to preformulation studies. AAPSPharmSciTech 10, (2), 649-659, 2009.
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 22
![Page 21: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/21.jpg)
Review Paper
52 Sarisuta N; Lawanprasert P; Puttipipatkhachorn S;Srikummoon K, The influence of drug-excipient anddrug-polymer interactions on butt adhesive strengthof Ranitidine Hydrochloride film-coated tablets.Drug Dev. Ind. Pharm. 32, 463-471, 2006.
53 Tonder ECV; Lotter AP; Botha SA, Compatibilitystudy between Doxylamine Succinate with otherdrugs and excipients using differntial scanningcalorimetry. Drug Dev. Ind. Pharm. 16, 2125-2133,1990.
54 Flemming A; Picker-Freyer KM, Compaction oflactose drug mixtures: Quantification of the extentof incompatibility by FT-Raman spectroscopy. Eur.J. Pharm. Biopharm. 68, (3), 802-810, 2008.
55 Misra M; Misra AK; Panpalia GM, Interaction studybetween pefloxacin mesylate and some diluentsusing DSC supported with isothermal method. J.Therm. Anal. Cal. 89, 803–808, 2007.
56 Verma RK; Garg S, Selection of excipients forextended release formulations of glipizide throughdrug–excipient compatibility testing. J. Pharm.Biomed. Anal. 38, 633–644, 2005.
57 Agatonovic-Kustrin S; Markovic N; Ginic-MarkovicM; Mangan M; Glass BD, Compatibility studiesbetween mannitol and omeprazole sodium isomers.J. Pharm. Biomed. Anal. 48, 356–360, 2008.
58 Barboza F; Vecchia DD; Tagliari MP; Silva MAS;Stulzer HK, Differential scanning calorimetry as ascreening technique in compatibility studies ofA cyc lov ir ex tend ed re le a se fo rm u la t ions .Pharmaceut. Chem. J. 43, 363-368, 2009.
59 Jaminet F; Louis G, Influence de quelqueslubrifiants sur la stabilite de l’Aspirine dans lescomprimes. Pharm. Acta Helv. 43, 153-157, 1968.
60 Miller TA; York P, Pharmaceutical tablet lubrication.Int. J. Pharm. 41, 1-19, 1988.
61 Wissing S; Craig DQM; Barker SA; Moore WD, Aninvestigation into the use of stepwise isothermal highsensitivity DSC as a means of detecting drug-excipient incompatibility. Int. J. Pharm. 199, (2),141-150, 2000.
62 Harding L; Qi S; Hill G; Reading M; Craig DQM,The development of microthermal analysis andphotothe rm al m ic rospectroscopy as nove lapproaches to drug–excipient compatibility studies.Int. J. Pharm. 354, 149–157, 2008.
63 Marini A; Berbenni V; Pegoretti M; Bruni G;Cofrancesco P; Sinistri C; Villa M, Drug excipientcompatibility studies by physico chemicaltechniques. The case of atenolol. J. Therm. Anal.Cal. 73, 547-561, 2003.
64 Phipps MA; Winnike RA, Use of isothermalmicrocalorimetry in the early detection of potential
drug formulation incompatibilities. Proc. WorkshopMicrocalorim. Energ. Mater., M1-M14, 1997.
65 Freire FD; Aragao CFS; Moura TFAdLe; R. FN,Compatibility study between chlorpropamide andexcipients in their physical mixtures. J. Therm. Anal.Calorim. 97, 355-357, 2009.
66 Cides LCS; Araújo AAS; Santos-Filho M; Matos JR,Thermal behaviour, compatibility study anddecomposition kinetics of glimepiride underisothermal and non-isothermal conditions. J. Therm.Anal. Cal. 84, (2), 441-445, 2006.
67 Oliveira GGG; Ferraz HG; Matos JSR,Thermoanalytical study of glibenclamide andexcipients. J. Therm. Anal. Cal. 79, 267-270, 2005.
68 Cheng W-T; Wang S-L; Lin S-Y, Solid-stateinteraction study on the captopril/lubricants systemsaccelerated by grinding process. J. Phys. Chem. 69,(4), 1007-1016, 2008.
69 Stulzer HK; Rodrigues PO; Cardoso TM; MatosJSR; Silva MAS, Compatibility studies betweenCaptopril and pharmaceutical excipients used intablets formulations. J. Therm. Anal. Cal. 91,323–328, 2008.
70 Strickley RG; Visor GC; Lin L; Gu L, Anunexpected pH effect on the stability of moexiprillyophilized powder. Pharm. Res. 6, 971-975, 1989.
71 El-Shattawy HH; Kildsig DO; Peck GE,C ep h a le x in -d irec t com press io n e x c ip ie n ts :Preformulation stability screening using differentialscanning calorimetry. Drug Dev. Ind. Pharm. 8, 897-909, 1982.
72 El-Shattawy HH; Kildsig DO; Peck GE,Erythromycin - Direct compression excipients:Preformulation stability screening using differentialccanning calorimetry Drug Dev. Ind. Pharm. 8,937–947, 1982.
73 El-Shattawy HH, Nalidixic acid - Directcompression excipients, preformulation stabilityscreening using differential scanning calorimetryDrug Dev. Ind. Pharm. 10, 491–504, 1984.
74 Jacobson H; Reier G, Application of differentialthermal analysis to compatibility and stabilityproblems in penicillin-stearic acid mixtures. J.Pharm. Sci. 58, 631-633, 1969.
75 Malan CEP; de Villiers MM; Lotter AP, Evaluation of compatibility of tablet excipients withalbendazole and closantel using DSC and HPLC.Drug Dev. Ind. Pharm. 23, 533-537, 1997.
76 Cunha-Filho MSS; Martýnez-Pacheco R; Landin M,Compatibility of the antitumoral â-lapachone withdifferent solid dosage forms excipients. J. Pharm.Biomed. Anal. 45, 590-598, 2007.
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 23
![Page 22: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/22.jpg)
Review Paper
77 Doser KH; Glanzer K; Loffler U Pharmaceuticalformulation for salts of monobasic acids withclopidogrel. 2007/0048370 A1, Mar. 1, 2007, 2007.
78 Voigt R; Pergande G; Keipert S, Comparativestudies on the study of drug-excipient interactionswith vapor pressure osmometry and equilibriumdialysis. Pharmazie 39, (11), 760-763, 1984.
79 Bruni G; Berbenni V; Milanese C; Girella A; MariniA, Drug-excipient compatibility studies in binary andternary mixtures by physico-chemical techniques. J.Therm. Anal. Cal., 102, 193-201, 2010.
80 Kiss D; Zelkó R; Novák C; Éhen Z, Application ofDSC and NIRS to study the compatibility ofmetronidazole with different pharmaceuticalexcipients. J. Therm. Anal. Cal. 84, 447-451, 2006.
81 Jin P; Madieh S; Augsburger LL, The solution andsolid state stability and excipient compatibility ofParthenolide in Feverfew. AAPS PharmSciTech 8,E1-E6, 2007.
82 Indrayanto G; Mugihardjo; Handayani R,Compatibility study between famotidine and someexcipients using differential scanning calorimetry.Drug Dev. Ind. Pharm. 20, 911-920, 1994.
83 Pignatello R; Ferro M; Puglisi G, Preparation ofsolid dispersions of nonsteroidal anti-inflammatorydrugs with acrylic polymers and studies onmechanisms of drug-polymer interactions. AAPSPharmSciTech 3, (2), 1-11 [article 10], 2002.http://www.aapspharmscitech.org/articles/pt0302/pt030210/pt030210.pdf
84 Pignatello R; Ferro M; Guidi GD; Salemi G;Vandelli MA; Guccione S; Geppi M; Forte C; PuglisiG, Preparation, characterisation and photosensitivitystudies of solid dispersions of diflunisal andEudragit RS100 and RL100. Int. J. Pharm., (218),27–42, 2001.
85 Gordon RE; VanKoevering CL; Reits DJ,Utilization of differential scanning calorimetry in thecompatibility screening of ibuprofen with thestearate lubricants and construction of phasediagrams. Int. J. Pharm. 21, 99-105, 1984.
86 Pignatello R; Spadaro D; Vandelli MA; Forni F;Puglisi G, Characterization of the mechanism ofinteraction in Ibuprofen - Eudragit RL100coevaporates. Drug Dev. Ind. Pharm. 30, 277–288,2004.
87 Cotton ML; Wu DW; Vadas EB, Drug-excipientinteraction study of enalapril maleate using thermalanalysis and scanning electron microscopy. Int. J.Pharm. 40, 129-142, 1987.
88 Devi MV; Babu PSSK, Drug-excipient interactionstudies on enalapril maleate Int. J. Pharm. Excipients2, 153-158 2000.
89 Dong Z; Choi DS, Hydroxypropyl methylcelluloseacetate succ inate : Potentia l drug–excipientincompatibility. AAPS PharmSciTech 9, (3), 991-997, 2008.
90 Teraoka R; Matsushima Y; Sugimoto I; Inoue K;Morita S-y; Kitagawa S, Effect of pharmaceuticalexcipients on the stability of Trichlormethiazidetablets under humid conditions. Chem. Pharm. Bull.57, (12), 1343-1347, 2009.
91 Cory W.C; Harris C; Martinez S, Accelerateddegradation of ibuprofen in tablets. Pharm. Dev.Technol., 15, 636-643, 2010.
92 Vecchio S; Rodante F; Tomassetti M, Thermalstability of disodium and calcium phosphomycin andthe effects of the excipients evaluated by thermalanalysis. J. Pharm. Biomed. Anal. 24, 1111-1123,2001.
93 Lieberman HH; Lachman L; Schwartz JB,Pharmaceutical dosage forms: Tablets. In 2ndEdition ed.; Lieberman HH; Lachman L; SchwartzJB, Eds. Marcel Dekker, Inc.: NewYork, Basel,1989; Vol. I, p 557.
94 Sabnis S; Rege P; Block LH, Use of chitosan incompressed tablets of diclofenac sodium: Inhibitionof drug release in an acidic environment. Pharm.Dev. Technol. 2, (3), 243-255, 1997.
95 Drebushchak VA; Shakhtshneider TP; Apenina SA;Medvedeva AS; Safronova LP; Boldyrev VV,Thermoanalytical investigation of drug-excipientinteraction. Part II. Activated mixtures of piroxicamwith cellulose and chitosan. J. Therm. Anal. Cal. 86,303–309, 2006.
96 Kararli TT; Needham TE; Seul CJ; Finnegan PM,Solid state interaction of magnesium oxide andibuprofen to form a salt. Pharm. Res. 6, 804–808,1989.
97 Yuan L-C; Dahl TC; Oliyai R, Effect of carbonatesalts on the kinetics of acid-catalyzed dimerization ofadefovir dipivoxil. Pharm. Res. 17, 1098-1103, 2000.
98 Moreton RC, Excipient interactions. In Excipientdevelopemnt for pharmaceutical, biotechnology anddrug delivery systems, Katdare A; Chaubal M, Eds.Informa Healthcare USA, Inc: New York, 2006; p105.
99 B la u g S ; H u a n g W , I n t e r a c t io n o fdextroamphetamine sulfate with spraydried lactose.J. Pharm. Sci. 61, 1770-1775, 1972.
100 Hartauer KJ; Guillory JK, A comparison of diffusereflectance FTIR spectroscopy and DSC in thecharacterization of a drug excipient interaction.Drug Dev. Ind. Pharm. 17, 617-630, 1991.
101 Santos AFO; BasílioJr ID; Souza FSd; MedeirosAFD; Pinto MF; Santana DPd; Macedo RO,
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 24
![Page 23: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/23.jpg)
Review Paper
Application of thermal analysis of binary mixtureswith metformin. J. Therm. Anal. Cal. 93, (2), 361-364, 2008.
102 Cavatur R; Vemuri NM; Chrzan Z, Use ofisothermal microcalorimetry in pharmaceuticalpreformulation studies part III. Evaluation ofexcipient compatibility of a new chemical entity. J.Therm. Anal. Cal. 78, 63–72, 2004.
103 Verloop Q; Marais AF; deVilliers MM; LiebenbergW, Compatibility of sennoside A and B withpharmaceutical excipients. Pharmazie 59, 728-730,2004.
104 Ahlneck C; Zografi G, The molecular basis ofmoisture effects on the physical and chemicalstability of drugs in the solid state. Int. J. Pharm. 62,87–95, 1990.
105 Castello RA; Mattocks AM, Discoloration of tabletscontaining amines and lactose. J. Pharm. Sci. 51,106-108, 1962.
106 Mroso PN; Li Wan Po A; Irwin WJ, Solid statestability of aspirin in the presence of exciplents:kinetic interpretation, modelling and prediction. J.Pharm. Sci. 71, 1096-1101, 1982.
107 Reepmeyer JC; Kirchhoefer RD, Isolation ofsalicylsalicylic acid, acetylsalicylsalicylic acid, andacetylsalicylic anhydride from aspirin tablets byextraction and high-pressure liquid chromatography.J. Pharm. Sci. 68, 1167-1169, 1979.
108 Mitrevej A; Hollenbeck RG, Influence ofhydrophilic excipients on the interaction of aspirinand water. Int. J. Pharm. 14, 243-250, 1983.
109 Kornblum SS; Zoglio MA, Pharmaceuticalheterogeneous systems I. Hydrolysis of aspirin incombination with tablet lubricants in an aqueoussuspension. J. Pharm. Sci. 56, 1569-1575, 1967.
110 Nelson E; Eppich D; Carstensen JT, Topochemicaldecomposition patterns of aspirin. J. Pharm. Sci. 63,755-757, 1974.
111 Troup AE; Mitchner H, Degradation ofphenylephrine hydrochloride in tablet formulationscontaining aspirin. J. Pharm. Sci. 53, 375–379, 1964.
112 Jacobs AL; Dilatush AE; Weinstein S; WindheuserJJ, Formation of acetylcodeine from aspirin andcodeine. J. Pharm. Sci. 55, 893–895, 1966.
113 Koshy KT; Troup AE; Duvall RN; Conwell RN;Shankle LL, Acetylation of acetaminophen in tabletformulations containing aspirin. J. Pharm. Sci. 56,1117–1121, 1967.
114 Kartal A; Björkqvist M; Lehto V-P; Juppo AM;Marvola M; Sivén M, Compatibility of chewing gumexcipients with the amino acid L-cysteine andstability of the active substance in directly
compressed chewing gum formulation. J. Pharm.Pharmacol. 60, 1131-1138, 2008.
115 Zoglio MA; Maulding HV; Haller RM; Briggen S,Pharm aceutica l heterogeneous systems III.Inhibition of stearate lubricant induced degradationof aspirin by the use of certain organic acids. J.Pharm. Sci. 57, 1877-1880, 1968.
116 Garg A; Singh S; Rao VU; Bindu K;Balasubramaniam J, Solid State Interaction ofRaloxifene HCl with Different Hydrophilic CarriersDuring Co-grinding and its Effect on DissolutionRate. Drug Dev. Ind. Pharm. 35, 455-470, 2009.
117 Chan AS Fluoride stability in dicalcium phosphatedihydrate composition. United States Patent5037636, 1991.
118 Thakur AB; Chen X; Bugay DE; Serajuddin ATM,Solid state incompatibility of dicalcium phosphatedihydrate with the sodium salt of a poorly water-soluble drug. Pharm. Res. 11 (Supl.), S166, 1994.
119 Stroyer A; McGinity JW; Leopard CS, Solid StateInteractions between the Proton Pump InhibitorOmeprazole and Various Enteric Coating Polymers.J. Pharm. Sci. 95, 1342-1353, 2006.
120 Rezende RLO; Santoro MIRM; Matos JR, Stabilityand compatibility study of Enalapril maleate usingthermoanalytical techniques. J. Therm. Anal. Cal. 93,881-886, 2008.
121 Jun HW; Whitworth CW; Luzzi LA, Decompositionof aspirin in polyethylene glycols. J. Pharm. Sci. 61,1160-1162, 1972.
122 Whitworth CW; Luzzi LA; Thompson BB; Jun HW,Stability of aspirin in liquid and semisolid bases II:Effect of fatty additives on stability in a polyethyleneglycol base. J. Pharm. Sci. 62, 1372-1374, 1973.
123 Ha E; Wang W; Wang J, Peroxide formation inpolysorbate 80 and protein stability. J. Pharm. Sci.91, 2252-2264, 2002.
124 Ilium L, Chitosan and its use as a pharmaceuticalexcipient. Pharm. Res. 15, 1326-1331, 1998.
125 Patel H; Stalcup A; Dansereau R; Sakr A, The effectof excipients on the stability of levothyroxinesodium pentahydrate tablets. Int. J. Pharm. 264, 35-43, 2003.
126 Kumar V; Shah RP; Malik S; Singh S, Compatibilityof atenolol with excipients: LC–M S/TO Fcharac te r ization of degradat ion/ in te rac t ionproducts, and mechanisms of their formation. J.Pharm. Biomed. Anal. 49, 880–888, 2009.
127 Lira AM; Araujo AAS; Basilio IDJ; Santos BLL;Santana DP; Macedo RO, Compatibility studies oflapachol with pharmaceutical excipients for the
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 25
![Page 24: Interactions and incompatibilities of pharmaceutical](https://reader031.vdocuments.us/reader031/viewer/2022020706/61fc8c128d33c02b785e7184/html5/thumbnails/24.jpg)
Review Paper
development of topical formulations. Thermochim.Acta 457, (1-2), 1-6, 2007.
128 Moyano MA; Broussalis AM; Segall AI, Thermalanalysis of lipoic acid and evaluation of thecompatibility with excipientes. J. Therm. Anal.Calorim., 99, 631-637, 2010.
129 Alexander KS; Pudipeddi M; Parker GA, Stability ofhydralazine hydrochloride syrup compounded fromtablets. Am. J. Hosp. Pharm. 50, 683-686, 1993.
130 Munjal M; Stodghill SP; ElSohly MA; Repka MA,P o l y m e r i c s y s t e m s f o r a m o r p h o u s 9 -tetrahydrocannabinol produced by a hot-meltmethod. Part I: Chemical and thermal stabilityduring processing. J. Pharm. Sci. 95, (8), 1841-1853,2006.
This Journal is © IPEC-Americas Inc J. Excipients and Food Chem. 1 (3) 2010 - 26