pharmaceutical excipients-boolket for pharmacy students

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page-

PHARMACEUTICAL

EXCIPIENTS

Prof. Reza-ul Jalil

PHARMACEUTICAL EXCIPIENTS Prof. Reza-ul Jalil, Dept. of Pharma. Tech. DU. Page- 2

⇒ INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS ⇒ MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS ⇒ COLORING AGENTS ⇒ FLAVORING AGENTS ⇒ ANTIOXIDANTS ⇒ ANTIMICROBIAL PRESERVATIVES ⇒ SOLVENT / VEHICLE ⇒ SURFACTANTS ⇒ BUFFERS ⇒ EXCIPIENTS IN TABLETS ⇒ POLYMERS ⇒ FLAVORS AND FLAVOR MODIFIERS


DEFINITION OF EXCIPIENT

The term comes from the Latin word excipients, present participle of the verb excipere which means to receive, to gather, to take out. This refers to one of the properties of an excipient, which is to ensure that a medicinal product has the weight, consistency and volume necessary for the correct administration of the active principle to the patient. In 1957, excipients were defined as ‘the substance used as a medium for giving a medicament’, that is to say with simply the functions of an inert support of the active principle or principles. Again, in 1974 they are described as ‘any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug: a vehicle.

This historically somewhat limiting definition referred to those substances employed in the preparation of pills, a now obsolete pharmaceutical dosage form later replaced by tablets and capsules. Natural products, such as molasses and honey, were long employed in the preparation of pills up to 1940 and USP 10 also mentioned lactose, glucose, lycopodium, glycerin and gelatin.

To the function of simple vehicle, galenic science then added that of adjuvant in the carrying and release of the active principle of the formulation. Looking at the matter

from this angle, the United States’ National Formulary of 1994 states that an excipient is any component other than the active principle added intentionally to the medicinal formulation, or ‘everything in the formulation except the active drug’.

The following general criteria are essential for excipients: • physiological inertness; • physical and chemical stablility; • conformance to regulatory agency

requirements; • no interference with drug

bioavailability; • absence of pathogenic microbial

organisms; and • commercially available at low cost. In reality, no single excipient would satisfy all the criteria; therefore, a compromise of the different requirements has to be made. For example, although widely used in pharmaceutical tablet and capsule formulations as a diluent, lactose may not be suitable for patients who lack the intestinal enzyme lactase to break down the sugar, thus leading to the gastrointestinal tract symptoms such as cramps and diarrhea. The role of excipients varies substantially depending on the individual dosage form.

INTRODUCTION TO PHARMACEUTICAL EXCIPIENTS


ROLE OF EXCIPIENTS

Among these roles are to be remembered those of guaranteeing the stability, precision and accuracy of the dose, improving the organoleptic characteristics and the patient’s compliance. Modern pharmaceutical technology also requires verification of the physical state of the excipient, which is so important both in the manufacturing phase and to control the release of the active principle, with the object of improving the bioavailability and consequently the efficacy and tolerability of the medicinal drug.

Medicinal dosage forms, regardless of composition or mode of use, must meet the following requirements that underpin efficacy, safety, and quality:

1. Contain an accurate dose.

2. Be convenient to take or administer.

3. Provide the drug in a form for absorption or other delivery to the target.

4. Retain quality throughout the shelf life and usage period.

5. Be manufactured by a process that does not compromise performance and that is reproducible and economical.

Few if any active pharmaceutical ingredients have properties that allow incorporation in units that meet all these criteria. Therefore, it is necessary to add other materials to make good any shortfalls. Consequently, virtually every medicinal product is a combination of the drug substance and excipients.

These are indispensable components of medicinal products and, in most cases comprise the greatest proportion of the dosage unit. It goes without saying that knowledge of the composition, function, and behavior of excipients is a prerequisite to the successful design, development and manufacture of pharmaceutical dosage forms.

The requirements listed above can be

considered the prime reasons for including excipients in dosage forms since they relate directly to product performance. Issues such as regulatory acceptability, environmental effects and impact on cost of the product are also important selection criteria.

Accuracy of dose

Where the active ingredient is very potent (i.e., dose is low), it may be necessary to disperse the drug in a ‘‘diluent’’ or bulking agent. Otherwise, quantities being filled into capsules or dies for tableting may be so low that normal filling and other process variations translate to excessive variation in unit drug content. Likewise, low-dose medications for inhalation as dry powders may have the drug dispersed in or otherwise associated with an inert ‘‘carrier’’ or flow aid. For a diluent to function in this way it must form a homogenous blend with the drug. Otherwise accuracy of dose cannot be guaranteed.

Water may be considered a ‘‘diluent’’ in liquid presentations as it provides the required dose in a volume that can be accurately dispensed or administered. It is also invariably present in medications for topical or transdermal application. Water can be one of the most problematic companion materials in a dosage form because of its capability to promote hydrolysis, act as a vehicle for other molecular interactions, or simply be a medium for microbial growth. Such properties illustrate how a material that resolves one problem may pose others that in turn require the presence of additional excipients.

Liquid or semisolid preparations may require the presence of ancillary excipients to effect solvation or dispersion of the active ingredient. In particular, formulations containing drugs in the suspended state may require viscosity-enhancing agents or other additives to ensure that the drug remains homogenously dispersed. Otherwise, the accuracy of the dose may be compromised.


User or patient convenience

Drugs that are bitter or otherwise unpalatable, and administered as oral liquids may be unacceptable, particularly to younger patients. Compliance and therefore efficacy may be compromised unless the product can be made more palatable. Thus, sweeteners, flavors, or taste-masking agents may be present in liquid oral products, in chewable dosage forms, and in effervescent or dispersible tablets that are constituted as liquids prior to use.

Some drugs given by injection cause local pain due to high volume, tonicity, pH, etc. An additive that evinces a local anesthetic effect may relieve such discomfort. Benzyl alcohol is employed for this purpose.

Release of drug from the dosage

form

Once a medication is ingested, applied to a target area, or otherwise administered, the drug must leave the dosage form for absorption or other delivery to the target. This may involve the following:

⇒ Dissolution in the gastrointestinal (GI) tract following oral dosage.

⇒ Partitioning to the skin in the case of topical or transdermal preparations.

⇒ Passage to pulmonary or nasal cavities (inhalation products).

Excipients can ensure that such delivery is expeditious and consistent. Their presence may be even more crucial with more esoteric forms that must be delivered to a tissue, organ, or even specific cells. Researchers are developing excipients that act as ‘‘homing devices’’ to guide drugs to designated targets. Such approaches will be discussed later in this chapter. In its simplest form, designing

‘‘release’’ into a dosage form involves adding a disintegrant to the tablet or capsule formulation so that on ingestion the compact breaks up and drug is released for dissolution and absorption. In the case of hydrophobic drugs, dissolution

may be aided by wetting agents. More complex release patterns involve using excipients to modify release from the dosage form to delay onset of action or otherwise modify the pharmacokinetics of the drug, thereby maximizing efficacy or minimizing side effects.

Excipients can influence delivery from topical and transdermal medications. The propensity of the drug to migrate from the formulation to the application surface is affected by factors such as lipophilicity of the vehicle, drug solubility in the formulation, and

effects of additives on the barrier properties of the skin or mucosal surface.

Oral absorption enhancement

Oral absorption is indirectly aided by excipients that promote release of drug from the dosage form, or help dispersion and dissolution prior to passage to the systemic circulation. Excipients that promote absorption per se are less widely used. However, lipids have been used to enhance absorption of hydrophobic active ingredients. Dissolution or dispersion of drug in such materials provides a substrate for lipolysis, resulting in an emulsion of drug and lipid that provides enhanced surface area for dissolution and absorption.

Excipients that are bioadhesive or that swell on hydration can promote absorption by increased contact with epithelial surfaces, by prolonging residence time in the stomach, or by delaying intestinal transit. Cellulose ethers, gums of natural origin, and synthetic

acrylic acid polymers have been evaluated for such purposes. The range of materials


available and their differing viscoelastic and rheological behaviors mean that it is possible, by judicious admixture, to develop delivery units with balanced properties so that

adhesion, density, hydration, drug release rate, etc. can be tailored to the drug in question and the physiological characteristics of the target delivery site.

Enhancers for Other Modes of Absorption

Many physical and enzymatic barriers can prevent successful delivery of active pharmaceutical ingredients by non-invasive, non-oral routes. It is not surprising, therefore, that there is great interest in excipients that can overcome such obstacles. Transdermal delivery is a case in point. The skin, particularly the stratum corneum presents a formidable barrier to diffusion. Materials used to enhance its permeability have ranged from simple solvents such as ethanol or propylene glycol to aromatic chemicals such as terpenoids. Such penetration enhancers appear to work by disrupting the lipid domains in the stratum corneum that reduce permeability.

Entry via nasal or buccal mucosa allows the delivery of peptides or other labile drugs that are highly potent (low-dose drugs) and that do not have steep doseresponse relationships. Absorption enhancement requires increased contact time and reduced clearance rate (in the case of nasal delivery), thereby optimizing conditions for mucosal diffusion. Excipients that enhance nasal absorption include phospholipids to enhance mucosal permeability and agents that imbibe water and become mucoadhesive (e.g., glyceryl mono oleate). In addition, the gelling agents hydroxypropyl cellulose and polyacrylic acid promote absorption of insulin in dogs.

EXCIPIENTS AS STABILIZERS

Product quality can be compromised during manufacture, transport, storage or use. The causes of deterioration can be manifold and product-specific. They include microbial spoilage or chemical transformation of the active or physical changes that alter performance

in vivo. Deterioration can compromise safety or make the medication less attractive, which means it may not be used. Excipients can contribute to or cause such changes unless carefully screened for possible interactions in preformulation studies.

Stablization strategies include the following:

• Formulation with an excipient whose light absorption spectrum overlaps that of the photolabile drug. This is the so-called spectral overlay approach.

• Using an antioxidant in formulations that are susceptible to degradation by oxidation. This approach has been particularly successful in vitamin-containing products.

• Using an excipient that ‘‘hinders’’ association of groups in the same molecule, in adjacent molecules, or in the vehicle that can interact and cause degradation. There are several reports of cyclodextrins effecting such ‘‘steric stabilizations.’’ Polyethylene glycol also has been shown to stabilize an ointment formulation by preventing formation of inactive rearrangement products. Equally important stabilizers include preservatives in liquid products to prevent microbial growth and buffers to provide an environment conducive to good stability where degradation is pH-related. Chelating agents also are used as stabilizers to prevent heavy metals from catalyzing degradation.

EXCIPIENTS AS PROCESS AIDS

The vast majority of medicinal products are manufactured by high-speed, largely


automated processes for reasons that are related as much to safety and quality as to cost of goods. Excipients that aid in processing include the following:

• The almost universal use of lubricants such as stearates in tablets and capsules to reduce friction between moving parts during compression or compaction.

• Excipients that aid powder flow in tablet or capsule manufacture. Materials such as colloidal silica improve flow from hopper to die and aid packdown in the die or capsule shell. Accuracy and consistency of fill and associated dose is thereby improved.

• Compression aids to help form a good compact, whether on dry granulation (slugging) prior to tableting or on tablet compression. Most are derived from plant, animal, or mineral origin (microcrystalline cellulose, lactose, or magnesium carbonate).

• Agents such as human or bovine serum albumin that are used in the manufacture of biotechnology- based products. These avoid adsorption of the protein to flexible tubing, filters, and other process equipment.

• Stabilizers to protect the drug from processing conditions that might otherwise be deleterious. It is common to use ‘‘cryoprotectants’’ such as sugars, polyhydric alcohols or dextrans in lyophilized parenteral biotechnology products to prevent inactivation during freezing.

• ‘‘Flow aids’’ also can help performance in cases where the delivery device is an integral part of the medication. Products for pulmonary delivery are often formulated as dry powders that are inhaled via the oral cavity. The fine-particle nature of the medicinal agent, which may be vital for efficient delivery to the bronchial target area, militates against good flow. Materials such as lactose or mannitol (of appropriate

particle size) can enhance flow or act as a ‘‘carrier’’ from the dose unit (usually a capsule) through the inhalation delivery device to the oral cavity on inspiration. They are widely used for these purposes in inhalation formulations of anti-asthmatic agents such as salbutamol and budesonide.

ORIGINS AND SOURCES OF

EXCIPIENTS

Excipients are of various origin:

1. animal (e.g. lactose, gelatin, stearic acid),

2. plant (e.g. starches, sugars, cellulose, arginates),

3. mineral (e.g. calcium phosphate, silica) and

4. synthesis (e.g. PEGs, polysorbates, povidone, etc.)

Their origin and use do not often guarantee the quality required by the pharmaceutical industry, which must therefore submit them to more thorough-going analytical controls. In order to carry out the numerous functions required, new classes of excipients have now become available, derived from old and new materials, alone or in combination, adapted to the manufacture of high-performance pharmaceutical dosage forms.

Looking at the matter from this angle, excipients can no longer be considered mere inert supports for the active principles, but essential functional components of a modern pharmaceutical formulation.

It is also to be borne in mind that the ratio of their weight to that of the active principles is usually very high in a formulation, and such as to cause possible action due to their mass.

Like pharmaceutical drugs, they too have their own thermo-dynamic activity


which, though generally low, can contribute to reactions leading to degradation or to interactions between the drug and the excipient.

Today it is reckoned that over one thousand different materials are used in the pharmaceutical industry to fulfil its various requirements such as diluents, bulking agents, disintegrants, lubricants, colouring agents, sweeteners, etc.

They are chemically heterogeneous compounds that go from simple molecules (water) to complex mixtures of natural, semisynthetic or synthetic substances.

From the regulatory point of view, may be subdivided into three categories.

1. In the first category (approved excipients) we find the compounds originating from the food industry (generally recognised as safe: GRAS) or that have been present in pharmaceutical products for a very long time.

2. The intermediate category (essentially new excipients) covers compounds obtained by means of the structural modification of the excipients already approved or those already used in the food or cosmetic industries.

3. The third category covers new compounds, never previously used in the pharmaceutical field and it is growing rapidly due to the present interest in modified-release formulations and the requirements of the modern high productivity compressing/tabletting machines.

PRINCIPAL REQUIREMENTS OF

EXCIPIENTS

Historically, the importance of excipients in pharmaceutical formulations has generally been underestimated, as they were cheap ingredients viewed solely as inert supports for medicaments. Today, this view is out-dated and, on the basis of

what we have said above, we may say that excipients are rather more than the sugar in the pill.

At this point we may well ask ourselves what the basic requirements of a modern pharmaceutical excipient are. In Fig. 1 the three essential requirements of active principles are compared with those of excipients. Fundamental for both are quality and safety. The requirement of therapeutic efficacy for drugs is replaced by that of functionality for excipients, defined as ‘the physical, physicochemical and biopharmaceutical properties’ of the same.

Safety has always been the most important requirement and the most studied when dealing with pharmaceutical drugs. Less attention has been devoted to the safety of excipients, because their inertia and innocuity were taken for granted.

To this end, we shall examine three issues that may compromise the safety of pharmaceuticals:

(a) production, distribution and use;

(b) pharmaceutical-excipient interactions; and

(c) toxicity, which may be the cause of frequent and sometimes notable ‘adverse effects’.

DRUG–EXCIPIENT INTERACTIONS

Excipients constitute the mass or greater volume in the usual enteral or parenteral formulations and, they often contain reactive functional groups that may give rise to chemical and physical transformations. Interactions occur more frequently between excipient and active principle than between excipient and excipient and these interactions can be of two types. The physical type of interaction can modify, for example, the speed of dissolution or the uniformity of the dosage of a solid formulation. Indeed, some materials can adsorb drugs to their


surfaces, thus increasing the active surface and consequently the wettability and speed of dissolution. The contrary effect may be encountered when the forces of attraction are strong, in which case the drug is released with difficulty and assimilation is compromised. One example is that of lipophilic lubricants (e.g. magnesium stearate) which, when finely dispersed on the particles of the active principle, can slow down dissolution and therefore bioavailability.

The chemical type of interaction, on the other hand, can lead to the degradation of the drug and/or the formation of the so-called degradation impurities. The most frequently encountered reaction is hydrolisis, because water is the preferred and prevalent solvent in liquid formulations. In solid forms which contain hygroscopic components, the presence of humidity must be controlled and reduced. Even the presence of oxygen, when activated by traces of catalysts (heavy metal ions, light, heat. . .), may give rise to oxide-reduction and the formation of free radicals (e.g. lipidic peroxidation). Other, less frequent, reactions are photolysis, isomerisation and polymerisation, which are more likely to occur with certain types of excipients, lowering the title of the active principle and generating dangerous impurities. One example is the presence of polymeric forms in beta-lactam drugs, such as ampicillin, which are thought to be responsible for dangerous allergic reactions. Ionisable pharmaceuticals may react with ionised soluble excipients giving rise to the formation of insoluble products due to charge interactions. In this way, sodium alginate and neomycin cation precipitate in an acqueous solution.

Another type of interaction may occur between the carbonilic groups of a widely-used excipient like poly-vinylpyrrolidone, and pharmaceuticals containing donor groups of hydrogen, like famotidine and atenolol, thus causing problems of incompatibility. Even silicon dioxide (SiO2), in anhydrous conditions, behaves

like a Lewis acid, giving rise to reactions such as hydrolisis, epimerisation, trans -esterification, etc. One example is the hydrolisis of the imino nitrogen link of nitrazepam with consequent disactivation of the drug.

However, when evaluating potential pharmaceutical-excipient interactions, it must however be considered that the kinetics of chemical reactions involving solutions are very high, whereas in the case of solid formulations they are low, if not negligible.

Despite the earlier account of excipients acting as stabilizers, it is fair to state that there are far more cases on record of excipients adversely affecting quality. Degradation may be caused by interaction between functional groups in the excipient and those associated with the drug. Many small-molecule drugs contain primary, secondary, or tertiary amino groups and these have the propensity to interact with aldehydic groups in sugars or volatile aldehydes present as residues.

Chemical interaction can result in degradation of the drug substance to inactive moieties with loss of efficacy where degradation is excessive. Even when degradation is modest, it is possible that the formed degradation products may compromise safety.

Physical interactions between drug and excipient also can compromise quality. Adsorption of drug by microcrystalline cellulose resulted in drug dissolution being less than complete.

Interaction between chloramphenicol stearate and colloidal silica during grinding led to polymorphic transformation.

Excipients may contribute to degradation even when not directly interacting with active moieties. Soluble materials may alter pH or ionic strength, thereby accelerating hydrolytic reactions in liquid presentations. Such effects may be accentuated during processing.


For instance, sterilization by autoclaving, while of short duration, may cause significant degradation product formation because of the high temperature involved. Dextrose is widely used in parenteral nutrition solutions or as a tonicity modifier in other parenterals. Sterilization by autoclaving can cause isomerization to fructose and formation of 5-hydroxymethyl furfulaldehyde in electrolyte-containing solutions.

At the other extremes of processing, succinate buffer was shown to crystallize during the freezing stage of lyophilization, with associated reduction of pH and unfolding of gamma interferon.

It is important to identify and characterize such ‘‘process stresses’’ during dosage-form development and tailor processing conditions accordingly.

Microcrystalline cellulose is a partially depolymerized cellulose that is part-crystalline/part non-crystalline and hygroscopic. Adsorbed water is not held in any ‘‘bound’’ state but will rapidly equilibrate with the environment during processing or storage. Thus, it is possible that in a dosage form, water can be sequestrated by a more hygroscopic active ingredient. If the drug is moisture sensitive, degradation may follow. Stabilization may be possible by drying prior to use, but loss of water may make it a less effective compression aid.

TOXICITY OF EXCIPIENTS

A discussion of the toxicity of the excipients employed in pharmaceutical formulations is certainly a difficult and extremely diversified task. To simplify matters, the subject may be organised as follows:

• toxic effects encountered in the whole population;

• toxic effects encountered only in specific populations.

Into the first category fall all the adverse effects proper to chemical, natural or synthetic substances when a certain dose is exceeded. The second category, however, has to do with phenomena that are often independent of, or only marginally dependent on, the dose. That is to say, they are events linked to specific characteristics of the subjects, such as genetically-transmitted pathologies (metabolic illnesses, among which phenylketonuria and lactose intolerance) or genetic predisposition (among which diabetes and allergic pathologies).

In principle, excipients ought to be subjected to the same toxicity studies as those requested for active principles, so as to protect the population from undesirable effects. This is assuredly applicable to many compounds, especially those that are used as food additives. However, other substances, that have been used for decades now, can be considered ‘safe’, given that no adverse effects have been encountered in man.

The excipients that have been authorised to be used as food additives have been evaluated as regards toxicology by the JECFA (Joint Expert Committee on Food Additives), which handles the evaluation of the risk from consuming additives or contaminants with food. In the case of additives, their use is voluntary and has a technological reason, exactly as in the case of pharmaceutical excipients, whereas contaminants are substances that can be vehicled by the food chain, given the ubiquitousness of the distribution of pollutants in the environment. In this article, our preferred source of toxicological data has been the JECFA’s conclusions, which take into particular consideration the results of long-term toxicological studies. The JECFA usually terminates its toxicological evaluations with the publication of an admissible daily intake (ADI), which represents the dose that does not carry risks to the population if taken every day for a life-time. This dose is expressed in mg (or microg) per kg of daily


weight per day. To establish the total daily dose, we should multiply this number by the bodily weight (usually reckoned as 60 kg). The value of the ADI is extrapolated from studies conducted in laboratory animals, dividing the highest dose without toxic effects in the animal by a safety factor (generally 100).

STABILITY OF EXCIPIENTS

Excipients can lose quality over time. Oils, paraffins, and flavors oxidize; cellulose gums may lose viscosity. Polymeric materials used in film coating or to modify release from the dosage form can age due to changes in glass transition temperature. This can lead to changes in elasticity, permeability, and hydration rate and associated changes in release properties or appearance. Preservatives such as benzoic acid or the para hydroxybenzoates are volatile and can be lost during product manufacture if the process involves heating.

Loss during product storage is also feasible if containers are permeable to passage of organic vapors. Acetate buffer is volatile at low pH and can be lost during the drying stages of lyophilization. Such behaviors reinforce the need to know the behaviors of excipients as well as of the active ingredient so that appropriate processing, storage conditions, and ‘‘use by’’ periods are stipulated where necessary.

IMPURITIES IN EXCIPIENTS

Excipients, like drug substances contain process residues, degradation products or other structural deviants formed during manufacture. Historically, it was not unusual for adulterants to be added to ‘‘bulk up’’ the commodity. Thankfully, a combination of better analytical techniques, vendor certification programs, and quality audit systems should mean that adulteration is largely a thing of the past. However, constant vigilance is

necessary. As recently as 1996, renal failure in children in Haiti was ascribed to use of glycerol contaminated with diethylene glycol in a liquid paracetamol product. Residues in excipients can affect quality and performance by interacting with the drug or other key components. Reducing sugar impurities in mannitol were responsible for the oxidative degradation of a cyclic heptapeptide.

CONCLUSIONS

Medicinal products can be considered a dosed combination of two types of constituents: the active principles and the excipients. The latter are the more important as far as weight is concerned, whether in solid forms, suspensions or solutions. The ideal excipient should be able to fill numerous and important functions, first among which that of guaranteeing the dose, stability and release of the active principle, and the patient’s ‘compliance’. Furthermore, it should possess particular chemical, physical and mechanical characteristics, so as to optimise the formulation’s ‘performance’ both during the manufacturing phase (manufacturability) and when used by the patient. This multiplicity of roles fits very ill with the traditional galenic view, that saw these ‘non-medicinal ingredients’ as chemically and pharmaco-toxicologically inert.

For a long time now, much attention has been paid to the required quality, efficacy and safety of active principles but only recently has the necessity emerged of examining not only the quality and performance but also the safety of the excipients. The problem is not simple if one considers that in countries like the United States, Japan and Europe there are now in use over a thousand excipients of varying origin, of more or less complex structure and belonging to different chemical classes. About one fifth of them are present in the respective Pharmacopoeiae, which list the pharmaceutical quality requirements but


not physical chemistry requirements, much less do they embark on questions of safety. Some information on this aspect may be gleaned from some texts. This under-estimation of the safety aspect is also a consequence of the fact that the first excipients were taken from the food industry and therefore considered ‘as safe’, or else they were already used in pharmaceutical products that had been in therapeutic use for a very long time. Today it is required that any chemically new product whose effects on man are not known must pass all the toxicological tests envisaged for an

active principle before it can be accepted as an excipient.

MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS

Acidifying agent Carriers for dry powder inhalers

Adhesive agent Solvents

Alkalizing agent Suppository bases

Adsorbent Surfactants

Aerosol propellants Suspending agents

Air displacement Sweetening agents

Anti foaming agents Tablet anti adherents

Antifungal preservatives Tablet binders

Antimicrobial preservatives Tablet/capsule diluents

Anti oxidants Tablet coating agents

Buffering agents Tablet disintegrants

Chelating agents Tablet glidants

Coating polymers Tablet lubricants

Coloring agents Tablet-coated, polishing agents

Emulsifying agents Tonicity agents

Flavoring agents Vehicles

Humectants Viscosity imparting agent

Ointment bases Wetting agent.


DEFINITION A material that is a dye, pigment, or other substance made by a process or similar artifice, or extracted, isolated, or otherwise derived with or without intermediate or final change of identity, from a vegetable, animal, mineral or other source and when added or applied to a food, drug, or cosmetic or to the human body or any part thereof, is capable (alone or through reaction with other substances) of imparting color. According to the Code of Federal Regulation of USA, color additives are: "Any substance, synthetic or otherwise, that when added or applied to food, drug, or cosmetic, or to the human body or any part thereof, is capable of imparting a color thereto". The use of coloring agents in pharmaceutical preparations for purpose of esthetics, as sensory adjunct to the flavors employed, and for purposes of product distinctiveness is important. The need to identify tablets in order to minimize the risk of confusion to the patient is an important factor to be considered in formulation. Color provides a relatively simple and convenient solution to this problem, so is widely used in tablet film coating. Colorants commonly used can be divided into three groups;

• the synthetic organic dyes and their respective lakes,

• inorganic pigments and

• miscellaneous natural colorants. In this context the use of the world dye implies a pigment implies a material that is insoluble but disperses in the film-coating solution.

Definition of Terms

Dyes are substances which impart color to an object; soluble dyes dissolve in specified liquids. Pigments are solid dyestuffs or mineral colors which unfold their color effect when finely dispersed. There are colored and white pigments. Colorants are preparations of dyestuffs meant for coloring. Color lakes are water-insoluble colorants obtained from soluble, organic dyes by salt formation (e.g. with aluminum or calcium) or surface fixation. The importance of colorants and flavoring substances is frequently undervalued, since they do not have a direct influence on the therapeutic effect of a dosage form. They do, however, enhance the acceptance of the product and therefore contribute substantially to a reliable therapy. Moreover, they are helpful in identifying unpacked dosage forms. The coloring process for sugar-

COLORING AGENTS

coated products and film-coated tablets is essentially the same.

• Aesthetic issues in dosage form design.

• Identification of the product by the manufacturer and therefore act as an aid (not a replacement) for existing GMP procedures. Colourants also aid in the identification of individual products by patients, particularly those taking multiple medication.

• They reinforce brand imaging by a manufacturer and thereby decrease the risk of counterfeiting.

• Colourants for film-coated tablets have to a greater or lesser extent opacifying properties which are useful when it is desired to optimize the ability of the coating to protect the active ingredient against the action of light.

Synthetic organic dyes and lakes

If the water-soluble organic dye is precipitated as its aluminum salt on to alumina by the addition of aluminum chloride then the pigment so formed is known as an aluminum salt by the addition of sodium hydroxide, bicarbonate or carbonate. The calculated quantity of dye necessary to achieve the required dye content is added to the alumina slurry and aluminum chloride solution added to effect lakeing. As soon as all the dye has been absorbed the precipitate is washed and filtered before being dry ground to the desired particle size. The pigmentary properties and the shade of the aluminum lakes depends a great deal on the preparation of the alumina, the processing conditions during the deposition of the dye and the extent of grinding. The amount of dye precipitated on the alumina is generally in the region of 10-40% by weight. All lakes contain approximately 15-23% by weight residual moisture, some of which is bound as water of hydration and all are insoluble in most solvents. Chemistry of color: Before the development of synthetic color additives, food and cosmetic colorants were obtained form mineral, animal and vegetable sources. Synthetic coloring agents, which were extracted from coal tar, a by-product of coal distillation, date back to the mid-19th century. By 1900, nearly 700 colors had been synthesized from aniline, a derivative of benzene produced from coal tar, and a major industry developed in the field of coal-tar dyes. Approximately 90% of color additives in prescription and OTC drugs are synthesized from aniline that is currently obtained from petroleum or petroleum products. The cause of color is attributed to the presence of certain chromophore groups within the color producing molecule. These chromophores include the -N = N- (AZO) = C = S (THIO) - N = O (NITROSO) - N = N+ - O- (AZOXY) - N+<O

O (NITRIO)


- CH =N - (AZO METHINE) = C = O (CARBONYL) = C = C (ETHENYL) Other substituent groups called AUXOCHROMES. They may be present in the molecule. This cause deepening of the color. The auxochromes include the basic - N<R

R - NH-R -NH2 acidic -SO3H -COOH, -OH The light of the visual spectrum which is not absorbed by the compound is transmitted or reflected and the compound assumes the color of the unabsorbed light. Thus if a compound absorbs all light of the visible spectrum except that viewed by the eye as red it will appear to be that color. Most of the dyes used in pharmacy, whether for their therapeutic or coloring properties, are salts of acid or basic dyes. The dye ion exhibits greater resonance than the parent molecule. The auxochromes are capable of forming ionizable salts. Any substance causing a decrease in the ionization will reduce the intensity of the color. This is the basis of many incompatibilities. DIFFERENT SOURCES OF COLORS: Synthetic There are many synthetic dyes currently used

(see below) Mineral Alumina (aluminum hydroxide) Red ferric oxide Yellow ferric oxide Titanium dioxide Azurite Carbon black Ultramarine blue (kaolin, sulfur, Na-carbonate,

carbon) Mica Pyrophylite Chromium oxide greens (chromic sesquioxide) Vegetable Canthaxanthin (natural beta carotene) Saffron (Crocus sativis) Indigo (Indigo plant) Chlorophyll (Green plant) Beet juice (beets) Xanthantine (microalgae) Tagetes (Aztec marigold petals) Caramel (burnt sugar) Grape color extract (Concord grapes) Alizarin (Madder plant) Annatto extract (annatto seed) Turmeric (Curcuma longat) Logwood extract (leguminous trees) Animal Guanine (from fish scales) Tyrian purple (snails) Cochineal (insect) Carmine (lake of cochineal) CLASSIFICATION

a) certified colors - synthetic and mineral colors approved by FDA. The Food, Drug and Cosmetic act of 1938 (US) broadened the scope of certified colors, containing three categories: F D & C, D & C and D & C for external use. It is again two types: -- Dyes -- Lakes -- Dyes are available in different form: Powder/ Granular/ Plating color/ Wet dry (blends)/ Diluted (cut blends)/ Liquid (aqueous)/ Liquid (non aqueous)/ Pests. -- FD&C dyes are water soluble ( and insoluble in most organic solvents). The dyes manifested their coloring power by being dissolved in the water medium. -- When anhydrous conditions are of important considerations, glycerin and propylene glycol are used as solvent. -- dyes are made soluble in glycerin and then propylene glycol. -- Only few dyes are soluble in alcohol. -- Good coloring technology recommends that the dyes solubilized before addition of colored product. However, it is often possible when water is added in the process, to add the dry color to the batch and depends upon the added moisture and heat to dissolve the color in processing. FD&C lakes: The color regulations defined FD&C lake as "Extension on a substratum of alumina, or a salt prepared from one of the water soluble straight colors by combining such color with the basic radical aluminum or calcium". The alumina hydrate or aluminum hydroxide substratum is insoluble so what is produced is an insoluble form of the dye - a pigment. Dye color by being dissolved in the solvent and the pigment (lake) by dispersion. b) uncertified colors - most natural colors. Chemical classification of dyes: 1. Acridine Dyes - Acriflavine 2. Azo dyes -Scarlet red, FD&C Red 1, Red 2, Orange 2. 3. Phthalein Dyes - FD&C red 3 4. Thiazine dyes - Methylene blue 5. Triphenylmethane - FD&C green 1, green 2 6. Nitro dyes - FD&C yellow 1, yellow 2 7. Indigo dyes - FD&C blue 2 Stability of dyes:


-- In general the certified colors can be said to be stable for most uses. In the dye stage no degradation has been noticed (other than loss in dye strength by absorbing moisture) in storage for 15 years. -- With the exception of FD&C Blue no-2 and FD&C red no-3, the light stability of the dye in the finished product is good. -- Two areas, in which the majority of the certified FD&C colors show instability are i) in combination with reducing agent and ii) retorted protein materials. -- The azo triphenyl methane dyes are easily reduced to colorless compounds. The ascorbic acid is a such reducing agent. -- Contact with metals, such as, zinc, copper, tin, aluminum, etc. are the factors of color fading. The use of EDTA serves as a protection of color fading. Safety of dyes: Some examples:

• Lash Lure, a coal-tar dye that was popular in 1930's for eyebrows and eyelashes, in a few cases caused devastating effects, such as, blindness and death.

• FD&C Red no 2 (amaranth) caused cancer in rats, reported by Russians in 1970's. In 1976, amaranth as well as FD&C Red no 4 and Carbon black were delisted.

• FD&C yellow no 5 (Tartrazine) was suspected of producing allergic-type reactions, including asthmatic symptoms, urticaria, angioedema, or nasal symptoms, especially in persons allergic to aspirin. Since 1980, this color additive must be listed on the labels of food and OTC drugs to alert consumers who may be sensitive to it.

Coloring technology for pharmaceuticals: -- in addition to esthetics and certification status of a dye, a formulator must select the dyes to be used in a particular formula on the basis of the physical and chemical properties of the dyes available. These include: solubility, pH & pKa values, pH stability, light stability (photostable), thermal stability. -- the dye must be chemically stable in the environment of the other formulation ingredients and must not interfere with the solubility -- A colorant becomes an integral part of a pharmaceutical formulation, and its exact quantitative amount must be reproducible each time the formulation is prepared,or else the preparation would have a different appearance from batch to batch. -- colorant generally added to liquid preparations ranges between 0.0005 to 0.001% depending upon the colorant and the depth of color desired. -- in contrast, solid dosage forms such as tablets, capsules, sugar coated tablets, film coated tablets and chewable tablets contain approximately 0.1% dye.

-- whenever possible dyes are added to pharmaceutical preparations in the form of dilute solutions rather than as concentrated dry powders. This permits greater accuracy in measurement and more consistent color production. -- in case of tablets, the color may be sprayed on the formed tablet during the coating process,or the colorant may be admixed as part of the dry powder mixture for uncoated tablets.

ANTIOXIDANTS Substances that reduces or inhibits oxidation of chemicals and drugs in a formulation. PROPERTIES: 1. Effective in low concentration. 2. adequately soluble in the product. 3. non-toxic and non-irritant at the effective concentration. 4. odorless, tasteless and colorless. 5. decomposition products should be non-toxic and non irritant. 6. stable and effective over a wide range of pH. 7. compatible with the drug and other formulation ingredients. 8. non volatile. Classification of Antioxidants: A: Primary antioxidants: act by interfering with the propagationstep of the autoxidtion process. AH + R* -----> RH + A* AH + ROO* --------> ROOH + A* Subsequently the antioxidant radical is annihilated by combination with other antioxidant radical or some other free radical. A* + A* ------> AA A* + R* ------> AR It follwos that for effective stabilization against autoxidation, the A-H chemical bond should be weaker than the R-H bond of the oxidiziable substnce. However, if the bond is too weak, then the anitoxidant will be destroyed rapidly by reaction with atmospheric oxigen. AH + O2 ----------> A* + HO2* It is evident that a primary antioxidant is used up by taking part in the chain process instead of the drug.

ANTIOXIDANTS


Classification of Antioxidants

A. Primary antioxidants:

Quinol group

Hydroquinon

Tocopheorls

Hydroxychromans

Butylated hydroxy anisol

Butylated hydroxy toluene

Catechol group

Catechol

Pyrogallol

Nordihydroguaiaretic acid (NDGA)

Gallic acid

Ethyl gallate

Propyl gallate

Octyl gallate

Dodecyl gallate

Nitrogen containing substance

Diphenyl amines

Casein

Alkanolamine esters

Amino and hydroxy derivatives of p-phenyl amine diamine

Sulphur containing substances

Cysteine hydrochloride

B. Reducing agents

Potasium and sodium

metabilsulphiets-- for acidic solution

Bisulphites -- for solution of intermediate pH

Sulphites -- for unbuffered and alkaline pH

Other examples are:

Sulphurous acid

Hypophosphorous acid

Dextrose

C. Synergist

Water soluble

Citric acid

Tartaric acid

Phosphoric acid

Ascorbic acid

Water insoluble

Ascorbyl palmitate

Mono-isopropyl citrate

palmityl phosphate

Mono stearyl citrate


ANTIMICROBIAL PRESERVATIVES DEFINITION OF TERMS Disinfectants, antiseptics, and preservatives are chemicals that have the ability to destroy or inhibit the growth of microorganisms, and are used for this purpose. These and other terms commonly employed are defined as follows: _ Disinfectants: Chemical agents or formulations that are too irritant or toxic on body surfaces, but are used to reduce the level of microorganisms from the surface of inanimate objects to one that is safe for a defined purpose. _ Antiseptics: Chemical agents or formulations that can be used as an antimicrobial agents on body surfaces. _ Preservatives: Chemical agents or formulations that are capable of reducing the number of viable microorganisms within an object or field to a level that is safe for its designated use and will maintain the numbers of viable microorganisms at or below a level for the use/shelf-life of the product. _ Bacteriostasis: A state in which the growth of microorganisms is halted or inhibited. _ Bactericide: A chemical antimicrobial agent that reduces the viability of a population of microorganisms exposed to it. This term is meaningless without specifying the concentration range over which this effect is obtained; such concentration ranges will vary between different species of microorganisms. _ Bacteriostat: A chemical antimicrobial agent that can prevent the growth of microorganisms within an otherwise nutritious environment. This term is meaningless without specifying the concentration at which this effect is achieved. Bacteriostatic concentrations do vary between different species of microorganisms. It should be noted that terms such as bactericide and bacteriostat should be discouraged; in the USP and EP, the term ‘‘antimicrobial agent’’ has replaced these terms. Attributes desired for antimicrobial preservatives: - broad spectrum and non specific - continuing activity - rapid action - non-allergenic and non-sensitizing - non toxic - non irritant

ANTIMICROBIAL PRESERVATIVES

- compatible with other ingredients - stable against chemical degradation - solubel in common pharmaceutical vehicles - stable in sterilizing temperature - capable of incativation or nutrilization for sterility testing - non-volatile Important points: * inactivation of antimicribial agens can be accmplished

using polysorbate 80 (tween 80) or lecithin.

• Generally combinations of two gives better results than using single preservative.

PRESERVATIVE IDEALS At present there is no perfect preservative, and all materials are a compromise of a number of often contrary properties. The following are the properties of an ideal preservative compound and need to be considered when choosing a preservative. 1. Definable in chemical terms: Many of the existing preservatives, such as the quaternary ammonium compounds, are mixtures of various homologues. Often the activity obtained is a function of the mixture composition. Unless it is possible to define and control mixture composition, the performance of the agents will be variable, even if they conform to a pharmacopoeial specification. 2. Broad spectrum of activity: The compounds must possess a broad spectrum of antimicrobial activity against all species of microorganisms and also toward bacterial endospores. In practice, the only compounds that meet this requirement are formaldehyde, gluteraldehyde, hypochlorite, and ethylene oxide. All these compounds are highly irritant at sterilizing concentrations to be used in pharmaceutical products. Formaldehyde is, however, used at low concentrations in some shampoos; in these cases contact with the skin is short-lived and irritancy minimal. Agents such as quaternary ammonium compounds, phenolics, and the parabens group possess good activity against gram-positive bacteria but little or no activity toward spores. Certain gram-negative organisms such a Pseudomonas aeruginosa are virtually resistant to these agents. Generally, antifungal activity is difficult to obtain. Combinations of preservatives are sometimes employed to widen the spectrum of activity to include molds, bacteria, yeasts, and endospores. 3. Effectiveness: The compounds must be effective over a wide range of pH in order to be effective in all formulations. In practice, compounds are generally more active at either acid or alkaline pH. Thus, the pH of a formulation determines the types of preservative suitable for inclusion. 4. Stablility: The compounds must be stable to light and elevated temperatures for the expected shelf life of the


product. The effects of pH upon stability should be minimal. In this respect it is worth noting that the preservative Bronopol is stable only in the dark and at an acid pH. Under alkaline conditions or in the light it rapidly decomposes to give formaldehyde at concentrations that would be ineffective as a preservative. 5. Solubility: Preservatives should ideally be used at concentrations much lower than that of the main constituents of the formulation. Their solubility ought to be such that it is possible to add them as a concentrated solution and where there is no danger of creating a saturated solution. 6. Aesthetics: Preservatives should have no perceptible odor, color, or taste, which might affect the aesthetic qualities of the final product. This can be of crucial importance for a cosmetic product but is less important for medical ones. 7. Volatility: Preservatives should be non-volatile. Thus, chloroform is not an ideal preservative as it is lost from the formulation each time it is exposed to air. 8. Product incompatibility: Preservatives should not be incompatible with any of the likely excipients within the product formulation. This would include incompatibilities with the container material and also the active ingredients. In practice this is very difficult to achieve. 9. Toxicity: At the concentrations employed, the preservative should be non-irritant, not cause hypersensitivity reactions, and be non-toxic. In this respect, the site of application is critical. Relatively few compounds are approved for use in opthalmic products due to their high sensitivity towards xenobiotics. Also, compounds safe for use on intact skin might be hazardous for inclusion in parenteral products. 10. Solubility in oil: Preservatives must not be too oil soluble as this can produce problems in two and three-phase systems where the preservative accumulates in the oil and micellar phases and is unavailable for antimicrobial action in the biological (aqueous) phase. It is worth noting that the oil : water partition coefficient can alter as a function of pH and also as a function of the nature of the oil.

Preservative Con.(%) For oral use: Benzoic acid 0.1 Sodium benzoate 0.1 - 0.2 Methyl Paraben and salts 0.1 Propyl Paraben and salts 0.05 Butyl Paraben and salts 0.02 Alcohol 15 -20 Glycerin 45 Sorbic acid and salts 0.1 Propionic acid and salts

Dehydroacetic acid For parenteral and opthalmic prod-ucts:

Benzalkonium chloride 0.01 Benzothonium chloride 0.01 Benzyl alcohol 2 Chlorobutanol 0.5 Phenyl ethyl alcohol 0.5 Cresol 0.3 - 0.5 Chlorocresol 0.1 - 0.2 Methyl paraben 0.1 Propyl paraben 0.02 Phenol 0.5 Phenyl mercuric nitrate 0.002 Phenyl mercuric acetate 0.002 Thiomerosal 0.01 Polymyxin-B-Sulfate 1000 USP unit For topical applications: Benzoic acid Phenol Sorbic acid Alcohols (ethyl and propyl) Quarternary ammonium salts Mercurals

PRESERVATIVES FOR PHARMACEUTICAL DOSAGEFORMS


SOLVENT / VEHICLE Water: The vast majority of injectable products and oral liquid formulations are aqueous solutions because of the physiological compatibility of water with body tissues. Additionally, the high dielectric constant of water makes it possible to dissolve ionizable electrolytes, and its hydrogen-bonding potential facili-tates the solution of alcohols, aldehydes, ketones, and amines. The current USP has monographs for 1. Purified Water, 2. Water for Injec-tion (WFI), 3. Sterile WFI, 4. Bacteriostatic WFI, and 5. Sterile Water for Irrigation. Water Miscible Vehicles: (Non-aqueous Solvents) Cosolvents are defined as water-miscible organic solvents that are used in liquid drug formulations to

• increase the solubility of poorly water-soluble substances or to

• enhance the chemical stability of a drug. Cosolvency, then, refers to the technique of using cosolvents for the stated purposes; it is also commonly referred to as solvent blending. Cosolvency has been used as an approach for preparing liquid drug preparations throughout the history of drug formulation. Certain drugs of botanic origin were known to be poorly soluble in water and required formulation in water– ethanol mixtures in order to deliver an adequate dose of drug in a small volume of preparation. A common example of a class of formulation containing cosolvents is the elixir, which by definition is a sweetened, hydroalcoholic solution intended for oral use. Tinctures, which generally contain even higher amounts of alcohol, are another classic example of a liquid dosage form containing a cosolvent. The need to employ cosolvents in the formulation of new drugs as solutions for oral, parenteral, and topical use remains high, especially with the increasing structural complexity of new therapeutic agents. In many cases, cosolvency can increase the solubility of a non-polar drug up to several orders of magnitude above the aqueous solubility. This would be significant, for example, in a formulation problem where it might be necessary to increase the solubility of a drug 500-fold or more. The use of cosolvents to prepare solution formulations of non-polar drugs is a simple and potentially effective way to achieve high concentrations of drug. The primary disadvantages of cosolvency include the potential for biological effects and the potential for drugs that have been solubilized using cosolvents to precipitate

upon dilution with aqueous fluids. The biological effects of a cosolvent that may limit or eliminate its use in drug formulations include their general toxicity, target organ toxicity, tissue irritation, or tonicity with respect to biologic membranes. In addition, precipitation of drug upon dilution with aqueous media or during injection or application to mucous membranes must always be considered in deciding if a co-solvent can be used as a vehicle for poorly water-soluble drugs. When used as a method for increasing the chemical stability of a drug, cosolvents may be effective by one or two mechanisms. If a drug is susceptible to hydrolytic degradation, cosolvents may reduce the degradation of the drug by substituting for some or all of the water in the formulation. Alternatively, a cosolvent may enhance the stability of a drug by providing a less suitable environment for the transition state of the reactants, provided the transition state is more polar than the reactants themselves. A non-aqueous solvent must be selected with great care for it must not be irritating, toxic, or sensitizing, and it must not exert an adverse effect on the ingredients of the formulation. Solvents that are miscible with water, and that are usually used in combination with water as the vehicle, include 1. Dioxolanes, 2. Dimethylacetamide, 3. N-q3-hydroxyethyl)-lactamide, 4. Butylene glycol, 5. Polyethylene glycol 400 and 600, 6. Propylene glycol, 7. Glycerin, and 8. Ethyl alcohol. The most frequently used nonaqueous solvents are polyethylene glycol, propylene glycol, and fixed oils. These solvents have been reviewed elsewhere and the reader is referred to this review for further details. Non-aqueous Vehicles: Drugs that are insoluble in aqueous systems are often incor-porated in metabolizable oils. Steroids, hormones, and vitamins are incorporated in vegetable oils such as peanut, sesame, corn, olive, and cottonseed. Oil injections are only administered intramuscularly. There are strict speci-fications for the vegetable oils used in manufacturing intramuscular injections. Storage of these preparations is important if stability is to be maintained. For example, they should not be subjected to conditions above room tempera-ture for extended periods of time. Although the oils used for injections are of vegetable origin, federal regulations require that the specific oil be listed on the label of a product, because some patients have exhibited allergic re-sponses to certain vegetable oils. Water-immiscible solvents include 1. Fixed oils, 2. Ethyl oleate, 3. Isopropyl myristate, and 4. Benzyl benzoate.

SOLVENT / VEHICLE


Surfactants in Pharmaceutical Products Surface-active agents (surfactants) are substances which, at low concentrations, adsorb onto the surfaces or interfaces of a system and alter the surface or interfacial free energy and the surface or interfacial tension. Surface-active agents have a characteristic structure, possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. Thus surfactants are said to be amphipathic in nature. Surfactant classification Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main groups of surfactants are defined as follows: 1. Anionic surfactants, where the hydrophilic group carries a negative charge, such as carboxyl (RCOO_), sulphonate (RSO3_) or sulphate (ROSO3_). Examples of pharmaceutical importance include potassium laurate, and sodium lauryl sulphate. 2. Cationic surfactants, where the hydrophilic group carries a positive charge (e.g., quaternary ammonium halide. Examples of pharmaceutical importance include cetrimide, a mixture consisting mainly of tetradecyl, dodecyl and hexa decyl trimethyl ammonium bromides, as well as benzalkonium chloride, a mixture of

alkylbenzyl dimethyl ammonium Chlorides. 3. Ampholytic surfactants (also called zwitterionic surfactants), where the molecule contains, or can potentially contain, both a negative and a positive charge, (e.g., the sulfobetaines). Examples of pharmaceutical importance include N-Dodecyl-N, N-Dimethylbetaine. 4. Nonionic surfactants, where the hydrophile carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O–) groups. Examples of pharmaceutical importance include polyoxy ethylated glycolmonoethers (e.g., cetomacrogol), sorbitan esters (Spans) and polysorbates (Tweens). Applicatons of surfactants

• Liquid dosage forms- solubilizers for poorly soluble drugs-Miceller solubilization

• Suspensions- wettening agents for hydrophobic drugs

• Emulsions- emulsifying agents, Micro-emulsions

• Topical ointment- as base, improve spreading.

• Solid dosage forms- solubility enhancement or dissolution improvement of poorly soluble drugs

• Tablet coating- improvement of coating solution spredability

• Drug delivery- Lyposome, Niosomes.

• Preservatives- some cationinc surfactants act as preservative.

• Aerosols– wetting agents

SURFACTANTS IN PHARMACEUTICAL

PRODUCTS


Buffers It is well known that many drugs are unstable when ex-posed to certain acidic or basic conditions, and such in-formation is routinely gathered during the preformulation stage of development. When such instabilities are identi-fied, one tool of the formulation sciences is to include a buffering agent (or agents) in the dosage form with the hope that such excipients will impart sufficient stability to enable the formulation. The properties that enable buffer-ing agents to function as such is derived from their quali-ties as weak acids or bases, and have their roots in their respective ionic equilibria. A buffer can be defined as a solution that maintains an approximately equal pH value even if small amounts of acidic or basic substances are added. To function in this manner, a buffer solution will necessarily contain either an acid and its conjugate base, or a base and its conju-gate acid. Selection criteria for buffering agents:

1. The buffer must have adequate capacity in the desired pH range.

2. The buffer must be biologically safe for the intended use.

3. The buffer should have little or no deleterious effect on the stability of the final product.

4. The buffer should permit acceptable flavoring and col-oring of the product. Buffers in pharmaceutical systems It is well known that the stability of many active pharma-ceutical substances can be strongly dependent on the degree of acidity or basicity to which they are exposed, and that a change in pH can cause significant changes in the rate of degradation reactions. For such compounds, formulators commonly include a buffer system to ensure the stability of the drug substance either during the shelf life of the product, or during the period associated with its administration. In addition, preformulation scientists routinely use buffer systems to set the pH of a medium in which they intend to perform experimentation. For instance, the pH stability profile of a drug substance is routinely obtained through the use of buffers, and the pH dependence of solubility is frequently measured using buffered systems. However, the possibility that the buffer system itself may influence or alter the results must be considered in these studies.

BUFFERS

Buffers Concentration range (%)

Acetic acid 0.22

Adipic acid 1.0

Benzoic acid and sodium benzoate 5.0

Citric acid 0.5

Lactic acid 0.1

Maleic acid 1.6

Potassium phosphate 0.1

Sodium phosphate monobasic 1.7

Sodium phosphate dibasic 0.71

Sodium acetate 0.8

Sodium bicarbonate 0.005

Sodium carbonate 0.06

Sodium citrate 4.0

Sodium tartrate 1.2

Tartaric acid 0.65


For tablets and capsules, excipients are needed both for the facilitation of the tableting and capsule-filling process (e.g., glidants) and for the formulation (e.g., disintegrants). Except for diluents, which may be present in large quantity, the level of excipient use is usually limited to only a few percent and some lubricants will be required at <1%. Details of the types, uses, and mechanisms of action of various excipients for tablet and capsule production have been discussed at length in other articles in this encyclopedia. The types and functions of excipients for tablet production are summarized in Table 1. Although binders, lubricants, and antiadherents are specific for making tablets, other excipients in Table 1 are also used in capsule production for reasons similar to those for tablets. It is worth noting that some of these tableting excipients may exert effects in opposition to each other. For example, binders and lubricants, because of their respective bonding and waterproofing properties, may hinder the disintegration action of the disintegrants. In addition, some of these tableting excipients may possess

>1 function that may be similar (e.g., talc as lubricant and glidant) or opposite (e.g., starch as binder and disintegrant) to each other. Furthermore, the sequence of adding the excipients during tablet production depends on the function of the excipient. Whereas the diluents and the binders are to be mixed with the active ingredient early on for making granules, disintegrants may be added before granulation (i.e., inside the granules), and/or during the lubrication step (i.e., outside the granules) before tablet compression.

EXCIPIENTS IN TABLETS AND CAPSULES


A monomer is a small molecule that combines with other molecules of the same or different types to form a polymer. Since drawing a complete structure of a polymer is almost impossible, the structure of a polymer is displayed by showing the repeating unit (the monomer residue) and an “n” number that shows how many monomers are participating in the reaction. From the structural prospective, monomers are generally classified as olefinic (containing double bond) and functional (containing reactive functional groups) for which different polymerization methods are utilized. If two, three, four, or five monomers are attached to each other, the product is known as a dimer, trimer, tetramer, or pentamer, respectively. An oligomer contains from 30 to 100 monomeric units. Products containing more than 200 monomers are simply called a polymer (Fig. 20–1). In a traditional pharmaceutics area, such as tablet manufacturing, polymers are used as tablet binders to bind the excipients of the tablet. Modern or advanced pharmaceutical dosage forms utilize polymers for drug protection, taste masking, controlled release of a given drug, targeted delivery, increase drug bioavailability, and so on and so forth. Apart from solid dosage forms, polymers have found application in liquid dosage forms as rheology modifiers. They are used to control the viscosity of an aqueous solution or to stabilize suspensions or even for the granulation step in preparation of solid dosage forms.

Major application of polymers in current pharmaceutical field is for controlled drug release, which will be discussed in detail in the following sections. In the biomedical area, polymers are generally used as implants and are expected to perform longterm service. This requires that the polymers have unique properties that are not offered by polymers intended for general applications. Table 20–3 provides a list of polymers with their applications in pharmaceutical and biomedical industries. In general, the desirable polymer properties in pharmaceutical applications are film forming (coating), thickening (rheology modifier), gelling (controlled release), adhesion (binding), pH-dependent solubility (controlled release), solubility in organic solvents (taste masking), and barrier properties (protection and packaging). From the solubility standpoint, pharmaceutical polymers can be classified as water-soluble and water-insoluble (oilsoluble or organic soluble). The cellulose ethers with methyl and hydroxypropyl substitutions are water-soluble, whereas ethyl cellulose and a group of cellulose esters such as cellulose acetate butyrate or phthalate are organic soluble. Hydrocolloid gums are also used when solubility in water is desirable. The synthetic water-soluble polymers have also found extensive applications in pharmaceutical industries, among them polyethylene glycol, polyethylene glycol vinyl alcohol polymers, polyethylene oxide, polyvinyl pyrrolidone, and polyacrylate or polymethacrylate esters containing anionic and cationic functionalities are well-established.

POLYMERS


Flavors and Flavor Modifiers

The use of flavors and flavor modifiers to improve the taste and aroma of foods and pharmaceuticals is an art that dates back several centuries. In large measure, the practice is still the same today and, except for the advent of new semi-synthetic flavoring agents with improved stability, the field has remained relatively unchanged. In the analytical arena, the story is different. DEFINITION OF FLAVOR The sensory perceptions are both qualitative as well as quantitative and, therefore, can be measured. Webster’s New Collegiate Dictionary defines flavor as the ‘‘ . . . quality of something that affects the sense of taste, . . . the blend of taste and smell sensations evoked by a substance in the mouth.’’ This definition is correct, but incomplete, and should be redefined to include feeling factors.

1. “Flavor is the sensation produced by a material taken in the mouth, perceived principally by the senses of taste and smell, and also by the general pain, tactile, and temperature receptors in the mouth. Flavor also denotes the sum of the characteristics of the material which produces that sensation.”

2. Flavor is the complex effect of three components: taste, odor, and feeling factors. It is usually associated with the pleasure of savoring food or beverages and has, subsequently, suffered from considerable imprecision in definition. Flavor is a sensation with multidimensional components involving subjective and objective perceptions.

3. “ Flavor is one of the three main sensory properties which are decisive in the selection, acceptance, and ingestion of a food.”

CLASSIFICATION OF FLAVORING AGENTS Natural flavouring substances: Natural flavouring substances means flavouring substances obtained from plant or animal raw materials, by physical, microbiological or enzymatic processes. They can be either used in their natural state or processed for human consumption, but cannot contain any nature-identical or artificial flavouring substances. Nature-identical flavouring substances: Nature-identical substances means flavouring substances that are obtained by synthesis or isolated through chemical processes, which are chemically identical to flavouring substances naturally present in products intended for human consumption. They cannot contain any artificial flavouring substances. Artificial flavouring substances: Artificial flavouring substances means flavouring substances not identified in a natural product intended for human consumption, whether or not the product is processed. TASTE The four primary taste- Sweet, bitter, sour and saline- appea4r to be the result of partly of physicochemical and partly of psychological action. Taste partly depends on the ions which are produced in the mouth, but psychologists have demonstrated that sight (color) and sound also play a definite role when certain reflexes become conditioned through custom and association of sense perceptions. Thus, in the classic experiments of Pavlov demonstrating "conditiond

FLAVORS AND FLAVOR MODIFIERS


reflexs", the ringing of a bell or the showing circle of light caused the gastric juices of a dog to follow although no food was placed before it. Taste consists of four primary sensations: sweet, sour, bitter, and salty. Correspondingly, there are four different kinds of taste buds. These sensations are elicited by the tongue and interpreted by the brain. Certain areas of the tongue respond more readily to specific tastes than others. Sweet sensations are most easily detected at the tip of the tongue, whereas bitter ones are most readily detected at the back of the tongue. Sour sensations occur at the sides of the tongue, but salty sensations are usually detected at both the tip and at the sides of the tongue. During ingestion, taste buds react to soluble substances. The resulting sensations are transmitted to the brain by the ninth cranial (glossopharyngeal) nerve. The tenth and twelfth cranial nerves participate in this sensory reaction, but their role is limited. Correlation of chemical structure with taste: Sour taste- hydrogen ions. Characteristics of acids,

tannins, alum, phenol and lactons. Saltiness- simultaneos presence of anions and cations.

e.g KBr, NaCl, etc. Bitterness- high molecular weight salts are bitter. Alkalis

both base and salt, many drugs, Sweet- due to poly hydroxy compounds, poly

halogeneted aliphatic compounds, and "-amino acids. eg. glucose, sugars, glycerin, sorbitol,

Odor: The odor component of flavor is due to conscious or subconscious reactions to volatile substances, without which most foods would be lacking in taste appeal. By closing the nostrils while eating a mouthful of some flavored substance and immediately following this with another mouthful with the nostrils open, it may be shown that food could be rendered tasteless, as is often experienced by people suffering from the effects of a

head cold. There are many varieties of odorants, but a universally accepted structure–activity relationship of these has not been established. Yet, there is evidence that odor may involve specific receptor interactions, suggesting that structural properties of odorants may be important in eliciting specific odor sensations. Feeling Factors: ‘‘Mouth feel’’ factors are critical in flavor perception. Examples include astringency, pepper bite, menthol cooling, and texture (e.g., softness or hardness as in candy). Sensations, such as crunch after biting into a crisp stick of celery or an apple, contribute to the overall flavor of foods. These mouth feel factors are also important in improving the organoleptic qualities of pharmaceuticals. FLAVORING AGENTS Flavoring agents may be classified as natural, artificial, or natural and artificial (N&A) by combining the all natural and synthetic flavors. Pharmaceutical flavors are available as liquids (e.g., essential oils, fluid extracts, tinctures, and distillates), solids (e.g., spraydried, crystalline vanillin, freeze-dried cinnamon powders, and dried lemon fluid extract), and pastes (e.g., soft extracts, resins, and so-called concretes, which are brittle on the outside and soft on the inside). Liquid flavors are by far the most widely used because they diffuse readily into the substrate. They are available both as oily (e.g., essential oils) or non-oily liquids. Their texture is generally dependent on the solvent within which they are prepared. Fluid extracts may contain a single ingredient or a variety of compounded ingredients. Tinctures are obtained by maceration or percolation of specific herbs and spices in alcohol. Essential oils boil at elevated temperatures, but many cannot be directly distilled without decomposition. Vacuum, steam, and fractional or molecular distillation are often used for their manufacture. Fractional distillation removes traces of water, resinous materials, colors, terpenes, and sesquiterpenes from the distillate. This process improves solubility and enhances flavor intensity. Sesquiterpeneless oils are more soluble than terpeneless oils because of the removal of head and tail fractions (e.g., waxy residues). Most common sesquiterpeneless oils used in the pharmaceutical industry include oil of orange and oil of lemon. Oils and juices are obtained from plant sources by expression. Citrus essential oils are almost exclusively obtained by this method. Thoroughly washed unripe citrus fruits are cold pressed manually, or mechanically, to rupture oil cells in the rind. The oil is collected by draining and centrifuging. Manual operation is labor intensive and has been replaced by machines. FLAVOR SELECTION IN PHARMACEUTICAL PREPARATIONS A number of criteria are used to select flavors during formulation. Different flavor concentrations produce highly subjective sensations. Specific requirements for balance and fullness are dependent, in part, on the drug substance and the physical form of the product. For this reason, when selecting a flavor system, the

Cherry Honey Cinnamon Pineapple Coconut Cardamon Peach Butter Clove apricot Cocoa Anise Apple Milk Mint Banana Pepermint Strawberry Garlic Raspberry Zinger Grape Plum Black currant Orange Vanilla Mango Lemon

Flavor types


compounding pharmacist must take into account several variables upon which a desired response would depend. Some of these are product texture (e.g., viscosity of formulation, solid or liquid), water content, base vehicle or substrate, and taste of the subject drug. Notable specific examples to consider are: _ Immediate flavor identity from the formulation as it is ingested. _ Compatible mouth feel factors and rapid development of a fully blended flavor in the mouth during ingestion of the product. _ Absence of ‘‘off’’ notes in the mouth and a mild transient aftertaste during ingestion of the product. The selection of a flavor system, thus, requires an extensive evaluation of a number of organoleptic qualities. Vehicle components within which the drug is presented have a significant bearing on the performance of the flavor system. Of these, the sweetener is perhaps the most relevant. Sweeteners The most commonly used sweeteners are sucrose, glucose, fructose, sorbitol, and glycerin. Using sucrose (sugar) as a standard, with 100 units of sweetness, Table 6 lists the relative intensities of other sweeteners. Glycerin, glucose, sorbitol, and sucrose have limited use in solid dosage forms (e.g., tablets) because the materials are hygroscopic. Mannitol is used more often in tablet manufacture. Besides being less hygroscopic, it has a negative heat of solution. For this reason, chewable tablets containing mannitol have a pleasant cooling sweet taste, which complements flavor quality. The artificial sweetener saccharin is widely used in foods and pharmaceuticals. It is approximately 350_ as sweet as sugar. It is sweet at very low concentrations (equivalent to about 5–10% sugar) but bitter at higher concentrations. Approximately 20% of the population are ‘‘saccharin sensitive;’’ that is, they perceive saccharin to be bitter even at low concentrations. Upon repeated tasting, saccharin becomes less sweet and increasingly bitter. By the third or fourth tasting, solutions of relatively low concentrations are often no longer sweet to the saccharin-sensitive person. The artificial sweeteners, cyclamate and aspartame, are about 30_ as sweet as sugar, but like saccharin, their sweet–bitter profiles are concentration dependent. Aspartame does not have a significant bitter aftertaste when compared to saccharin and has gained in popularity. Cyclamates were banned in the 1970s because of carcinogenic concerns, which have, subsequently, been shown to be overstated. List of sugar substitutes The three primary compounds used as sugar substitutes in the United States are saccharin (e.g., Sweet'N Low), aspartame (e.g., Equal, NutraSweet) and sucralose (e.g., Splenda,Altern). Maltitol and sorbitol are often used, frequently in toothpaste, mouth wash, and in foods such as "no sugar added" ice cream. Erythritol is gaining momentum as a replacement for these other sugar alcohols in foods as it is much less likely to produce gastrointestinal distress when consumed in large amounts. In many other

countries xylitol, cyclamate and the herbal sweetener stevia are used extensively. Flavor Enhancers and Potentiators Flavor enhancers are used universally in the food and pharmaceutical industries. Sugar, carboxylic acids (e.g., citric, malic, and tartaric), common salt (NaCl), amino acids, some amino acid derivatives (e.g., monosodium glutamate—MSG), and spices (e.g., peppers) are most often employed. Although extremely effective with proteins and vegetables, MSG has limited use in pharmaceuticals because it is not a sweetener. Citric acid is most frequently used to enhance taste performance of both liquid and solid pharmaceutical products, as well as a variety of foods. Other acidic agents, such as malic and tartaric acids, are also used for flavor enhancement. In oral liquids, these acids contribute unique and complex organoleptic effects, increasing overall flavor quality. Common salt provides similar effects at its taste threshold level in liquid pharmaceuticals. Vanilla, for example, has a delicate bland flavor, which is effectively enhanced by salt. Taste-Masking Agents The flavoring industry has many proprietary products purported to have excellent taste-masking properties, which have been used with some success. Yet, there are a number of natural and artificial flavors that can be generally described to possess similar taste-masking effects. Of the many tastes that must be masked in pharmaceuticals, bitterness is most often encountered; to mask it completely is difficult. A tropical fruit has been used for centuries in central Africa to mask the bitter taste of native beers. This so-called ‘‘miracle berry’’ contains a glycoprotein that transiently and selectively binds to bitter taste buds. Due to stability challenges, attempts to isolate the compound for commercial exploitation have been unsuccessful. Yet, many fruit syrups are relatively stable in pharmaceuticals if formulated with antimicrobial preservative agents. Syrups of cinnamon, orange, citric acid, cherry, cocoa, wild


cherry, raspberry, or glycyrrhiza elixir can be used to effectively mask salty and bitter tastes in a number of drug products. The extent to which taste-masking may be achieved is not usually predictable due to complex interactions of other flavor elements in these products. The degree to which bitterness may be masked by these agents ranks in a descending order: cocoa syrup is most effective, followed by raspberry syrup, cherry, cinnamon, compound sarsaparilla, citric acid, licorice,

aromatic elixir, orange, and wild cherry. Sour and metallic tastes in pharmaceuticals also can be reasonably masked. Sour substances containing hydrochloric acid are most effectively neutralized with raspberry and other fruit syrups. Metallic tastes in oral liquid products (e.g., iron) are usually masked by extracts of gurana, a tropical fruit. Gurana flavor is used at concentrations ranging from 0.001 to about 0.5% and may be useful in solid products as well (e.g., chewable tablets and granules).

Natural sugar substitutes

SUCROSE

Sorbitol — 0.6× sweetness (by weight), 0.9× sweetness (by food energy), 0.65× energy density, E420

Glycerol — 0.6× sweetness (by weight), 0.55× sweetness (by food energy), 1.075× energy density, E422

Mannitol — 0.5× sweetness (by weight), 1.2× sweetness (by food energy), 0.4× energy density, E421

Erythritol — 0.7× sweetness (by weight), 14× sweetness of sucrose (by food energy), 0.05× energy density of sucrose

Glycyrrhizin — 50× sweetness (by weight)

Hydrogenated starch hydrolys-ates

— 0.4–0.9× sweetness (by weight), 0.5×–1.2× sweetness (by food energy), 0.75× energy density

Inulin

Isomalt — 0.45–0.65× sweetness (by weight), 0.9–1.3× sweetness (by food energy), 0.5× energy density, E953

Lactitol — 0.4× sweetness (by weight), 0.8× sweetness (by food energy), 0.5× energy density, E966

Maltitol — 0.9× sweetness (by weight), 1.7× sweetness (by food energy), 0.525× energy density, E965

Tagatose — 0.92× sweetness (by weight), 2.4× sweetness (by food energy), 0.38× energy density

Xylitol — 1.0× sweetness (by weight), 1.7× sweetness (by food energy), 0.6× energy density, E967

Plant extracts

Monatin — naturally-occurring sweetener isolated from the plant Sclerochiton ilicifolius

Stevia — 250× sweetness (by weight) - extracts known as rebiana, Truvia, PureVia; mainly containing rebaudioside A, a steviol glycoside

Monellin — protein, 3,000× sweetness (by weight); the sweetening ingredient in serendipity berries

Pentadin — protein, 500× sweetness (by weight)

Miraculin — protein, does not taste sweet by itself, but modifies taste receptors to make sour things taste sweet temporarily

Thaumatin — protein, 2,000× sweetness (by weight), E957

Brazzein — protein, 800× sweetness of sucrose (by weight)

Curculin — protein, 550× sweetness (by weight)

Mabinlin — protein, 100× sweetness (by weight)

Artificial sugar substitutes

Sucralose — 600× sweetness (by weight), Kaltame, Splenda, Tate & Lyle, E955, FDA Ap-proved 1998

Saccharin — 300× sweetness (by weight), E954, FDA Approved 1958

Aspartame — 160–200× sweetness (by weight), NutraSweet, E951, FDA Approved 1981

Neotame — 8,000× sweetness (by weight), NutraSweet, FDA Approved 2002

Salt of aspartame-acesulfame — 350× sweetness (by weight), Twinsweet, E962

Acesulfame potassium — 200× sweetness (by weight), Nutrinova, E950, FDA Approved 1988

Glucin — 300× sweetness (by weight)

Neohesperidin dihydrochalcone — 1,500× sweetness (by weight), E959

Alitame — 2,000× sweetness (by weight), Pfizer, Pending FDA Approval

Cyclamate — 30× sweetness (by weight), Abbott, E952, FDA Banned 1969

Dulcin — 250× sweetness (by weight), FDA Banned 1950


Ammonium Chloride-Acidulant

Fumaric Acid-Acidulant

Hydrochloric Acid-Acidulant

Malic Acid-Acidulant

Phosphoric Acid-Acidulant

Sulfuric Acid-Acidulant

Tartaric Acid-Acidulant

Aluminum Hydroxide Adjuvant-Adsorbant

Aluminum Oxide-Adsorbant

Aluminum Phosphate Adjuvant-Adsorbant

Attapulgite-Adsorbant

Colloidal Silicon Dioxide-Adsorbant

Hydrophobic Colloidal Silica-Adsorbant

Magnesium Oxide-Adsorbant

Dimethicone-Antifoaming Agent

Simethicone-Antifoaming Agent

Alpha Tocopherol-Antioxidant

Ascorbic Acid-Antioxidant

Ascorbyl Palmitate-Antioxidant

Butylated Hydroxyanisole-Antioxidant

Butylated Hydroxytoluene-Antioxidant

Butylparaben-Antioxidant

Erythorbic Acid-Antioxidant

Monothioglycerol-Antioxidant

Potassium Metabisulfite-Antioxidant

Propyl Gallate-Antioxidant

Sodium Ascorbate-Antioxidant

Sodium Formaldehyde Sulfoxylate-Antioxidant

Sodium Metabisulfite-Antioxidant

Sodium Sulfite-Antioxidant

Sodium Thiosulfate-Antioxidant

Sulfur Dioxide-Antioxidant

Potassium Alum-Astringent

Sodium Borate-Astringent

Denatonium Benzoate-Bittering Agent

Sucrose Octaacetate-Bittering Agent

Acetic Acid, Glacial-Buffering Agent

Adipic Acid-Buffering Agent

Ammonia Solution-Buffering Agent

Calcium Hydroxide-Buffering Agent

Citric Acid Monohydrate-Buffering Agent

Lactic Acid-Buffering Agent

Maleic Acid-Buffering Agent

Meglumine-Buffering Agent

Monoethanolamine-Buffering Agent

Potassium Citrate-Buffering Agent

Potassium Hydroxide-Buffering Agent

Sodium Carbonate-Buffering Agent

Sodium Citrate Dihydrate-Buffering Agent

Sodium Lactate-Buffering Agent

Sodium Phosphate, Dibasic-Buffering Agent

Sodium Phosphate, Monobasic-Buffering Agent

Boric Acid-Buffering Agent

Diethanolamine-Buffering Agent

Disodium Edetate-Chelating Agent

Edetic Acid-Chelating Agent

Pentetic Acid-Chelating Agent

Shellac-Coating Agent

Zein-Coating Agent

Iron Oxides-Color

Titanium Dioxide-Color-Pigment

Cyclodextrins-Complexing Agent

Hydroxypropyl Betadex-Complexing Agent

Sulfobutylether b-Cyclodextrin-Complexing Agent

Calcium Chloride-Desiccant

Chloroxylenol-Disinfectants

Lactose, Inhalation-Dpi-Diluent

Potassium Bicarbonate-Effervescent-Base

Sodium Bicarbonate-Effervescent-Base

Isopropyl Myristate-Emollient

Isopropyl Palmitate-Emollient

Mineral Oil-Emollient

Mineral Oil, Light-Emollient

Lecithin-Emulsifier

Cholesterol-Emulsifying Agent

Mineral Oil and Lanolin Alcohols-Emulsifying Agent

Octyldodecanol-Emulsifying Agent

Polyoxylglycerides-Emulsifying Agent

Triethanolamine-Emulsifying Agent

Vitamin E Polyethylene Glycol Succinate-Emulsifying Agent

Wax, Anionic Emulsifying-Emulsifying Agent

EXCIPIENT-Classification


Wax, Nonionic Emulsifying-Emulsifying Agent

Ethylene Glycol Stearates-Emulsion Stabilizer

Glyceryl Behenate-Emulsion Stabilizer

Glyceryl Monooleate-Emulsion Stabilizer

Glyceryl Monostearate-Emulsion Stabilizer

Glyceryl Palmitostearate-Emulsion Stabilizer

Ethyl Maltol-Flavoring Agent

Ethyl Vanillin-Flavoring Agent

Isomalt-Flavoring Agent

Leucine-Flavoring Agent

Maltol-Flavoring Agent

Menthol-Flavoring Agent

Methionine-Flavoring Agent

Monosodium Glutamate-Flavoring Agent

Vanillin-Flavoring Agent

Carbon Dioxide-Gas

Nitrogen-Gas

Acacia-Hydrocolloid

Alginic Acid-Hydrocolloid

Ammonium Alginate-Hydrocolloid

Calcium Alginate-Hydrocolloid

Carrageenan-Hydrocolloid

Chitosan-Hydrocolloid

Guar Gum-Hydrocolloid

Pectin-Hydrocolloid

Potassium Alginate-Hydrocolloid

Sodium Acetate-Hydrocolloid

Sodium Alginate-Hydrocolloid

Tragacanth-Hydrocolloid

Xanthan Gum-Hydrocolloid

Polacrilin Potassium-Ionexchange Resin

Almond Oil-Oily Vehicle

Canola Oil-Oily Vehicle

Castor Oil-Oily Vehicle

Coconut Oil-Oily Vehicle

Corn Oil-Oily Vehicle

Cottonseed Oil-Oily Vehicle

Ethyl Oleate-Oily Vehicle

Medium-chain Triglycerides-Oily Vehicle

Oleyl Alcohol-Oily Vehicle

Olive Oil-Oily Vehicle

Palmitic Acid-Oily Vehicle

Peanut Oil-Oily Vehicle

Safflower Oil-Oily Vehicle

Sesame Oil-Oily Vehicle

Soybean Oil-Oily Vehicle

Sunflower Oil-Oily Vehicle

Castor Oil, Hydrogenated-Ointment Base

Ceresin-Ointment Base

Cetostearyl Alcohol-Ointment Base

Cetyl Alcohol-Ointment Base

Lanolin-Ointment Base

Lanolin Alcohols-Ointment Base

Lanolin, Hydrous-Ointment Base

Paraffin-Ointment Base

Petrolatum-Ointment Base

Petrolatum and Lanolin Alcohols-Ointment Base

Sodium Hydroxide-Ph ADJUSTMENT

Acetyltributyl Citrate-Plasticizer

Acetyltriethyl Citrate-Plasticizer

Dibutyl Phthalate-Plasticizer

Dibutyl Sebacate-Plasticizer

Diethyl Phthalate-Plasticizer

Dimethyl Phthalate-Plasticizer

Triacetin-Plasticizer

Tributyl Citrate-Plasticizer

Triethyl Citrate-Plasticizer

Wax, Carnauba-Polishing Agent

Wax, White-Polishing Agent

Wax, Yellow-Polishing Agent

Aliphatic Polyesters-Polymer

Carbomer-Polymer

Cellulose Acetate-Polymer

Cellulose Acetate Phthalate-Polymer

Dextrin-Polymer

Ethylcellulose-Polymer

Ethylene Vinyl Acetate-Polymer

Gelatin-Polymer

Hydroxyethyl Cellulose-Polymer

Hydroxyethylmethyl Cellulose-Polymer

Hydroxypropyl Cellulose-Polymer

Hydroxypropyl Cellulose, Low-substituted-Polymer

Hydroxypropyl Starch-Polymer

Hypromellose-Polymer

Hypromellose Acetate Succinate-Polymer

Hypromellose Phthalate-Polymer

Methylcellulose-Polymer

Poloxamer-Polymer


Poly(DL-Lactic Acid)-Polymer

Poly(methyl vinyl ether/maleic anhydride)-Polymer

Polycarbophil-Polymer

Polydextrose-Polymer

Polyethylene Glycol-Polymer

Polyethylene Oxide-Polymer

Polymethacrylates-Polymer

Polyvinyl Acetate Phthalate-Polymer

Polyvinyl Alcohol-Polymer

Povidone-Polymer

Carboxymethylcellulose Sodium-Polymer

Carboxymethylcellulose Calcium-Polymer

Copovidone-Polymer

Potassium Sorbate-Preservative

Benzalkonium Chloride-Preservative

Benzethonium Chloride-Preservative

Benzoic Acid-Preservative

Benzyl Alcohol-Preservative

Benzyl Benzoate-Preservative

Bronopol-Preservative

Cetrimide-Preservative

Cetylpyridinium Chloride-Preservative

Chlorhexidine-Preservative

Chlorobutanol-Preservative

Chlorocresol-Preservative

Cresol-Preservative

Ethylparaben-Preservative

Hexetidine-Preservative

Imidurea-Preservative

Methylparaben-Preservative

Phenol-Preservative

Phenoxyethanol-Preservative

Phenylethyl Alcohol-Preservative

Phenylmercuric Acetate-Preservative

Phenylmercuric Borate-Preservative

Phenylmercuric Nitrate-Preservative

Potassium Benzoate-Preservative

Propionic Acid-Preservative

Propylparaben-Preservative

Propylparaben Sodium-Preservative

Sodium Benzoate-Preservative

Sodium Propionate-Preservative

Sorbic Acid-Preservative

Thimerosal-Preservative

Thymol-Preservative

Chlorodifluoroethane (HCFC)-Propellant

Chlorofluorocarbons (CFC)-Propellant

Difluoroethane (HFC)-Propellant

Dimethyl Ether-Propellant

Heptafluoropropane (HFC)-Propellant

Hydrocarbons (HC)-Propellant

Nitrous Oxide-Propellant

Tetrafluoroethane (HFC)-Propellant

Acetone-Solvent

Alcohol-Solvent

Butylene Glycol-Solvent

Cyclomethicone-Solvent

Dimethyl Sulfoxide-Solvent

Dimethylacetamide-Solvent

Ethyl Acetate-Solvent

Ethyl Lactate-Solvent

Glycerin-Solvent

Glycofurol-Solvent

Isopropyl Alcohol-Solvent

Propylene Carbonate-Solvent

Propylene Glycol-Solvent

Pyrrolidone-Solvent

Triolein-Solvent

Albumin-Stabilizer

Calcium Acetate-Stabilizer

Glycine-Stabilizer

Raffinose-Stabilizer

Trehalose-Stabilizer

Zinc Acetate-Stabilizer

Stearyl Alcohol-Stiffening Agent

Wax, Cetyl Esters-Stiffening Agent

Wax, Microcrystalline-Stiffening Agent

Suppository Bases, Hard Fat-Suppository Base

Docusate Sodium-Surfactant

Macrogol 15 Hydroxystearate-Surfactant

Phospholipids-Surfactant

Polyoxyethylene Alkyl Ethers-Surfactant

Polyoxyethylene Castor Oil Derivatives-Surfactant

Polyoxyethylene Sorbitan Fatty Acid Esters-Surfactant

Polyoxyethylene Stearates-Surfactant

Sodium Lauryl Sulfate-Surfactant

Sorbitan Esters (Sorbitan Fatty Acid Esters)-Surfactant

Bentonite-Suspending Agent


Calcium Silicate-Suspending Agent

Ceratonia-Suspending Agent

Hectorite-Suspending Agent

Kaolin-Suspending Agent

Magnesium Aluminum Silicate-Suspending Agent

Propylene Glycol Alginate-Suspending Agent

Saponite-Suspending Agent

Sodium Hyaluronate-Suspending Agent

Aspartame-Sweetening Agent

Dextrose-Sweetening Agent

Fructose-Sweetening Agent

Glucose, Liquid-Sweetening Agent

Lactitol-Sweetening Agent

Maltitol-Sweetening Agent

Maltitol Solution-Sweetening Agent

Maltose-Sweetening Agent

Mannitol-Sweetening Agent

Neohesperidin Dihydrochalcone-Sweetening Agent

Neotame-Sweetening Agent

Saccharin-Sweetening Agent

Saccharin Sodium-Sweetening Agent

Sodium Cyclamate-Sweetening Agent

Sorbitol-Sweetening Agent

Sucralose-Sweetening Agent

Sucrose-Sweetening Agent

Sugar, Confectioner’s-Sweetening Agent

Tagatose-Sweetening Agent

Thaumatin-Sweetening Agent

Xylitol-Sweetening Agent

Acesulfame Potassium-Sweetening Agent

Alitame-Sweetening Agent

Calcium Carbonate-Tablet Diluent

Calcium Lactate-Tablet Diluent

Calcium Phosphate, Dibasic Anhydrous-Tablet Diluent

Calcium Phosphate, Dibasic Dihydrate-Tablet Diluent

Calcium Phosphate, Tribasic-Tablet Diluent

Calcium Sulfate-Tablet Diluent

Cellulose, Microcrystalline-Tablet Diluent

Cellulose, Powdered-Tablet Diluent

Cellulose, Silicified Microcrystalline-Tablet Diluent

Starch-Tablet Diluent

Starch, Pregelatinized-Tablet Diluent

Corn Starch and Pregelatinized Starch-Tablet Diluent

Dextrates-Tablet Diluent

Erythritol-Tablet Diluent

Inulin-Tablet Diluent

Lactose, Anhydrous-Tablet Diluent

Lactose, Monohydrate-Tablet Diluent

Lactose, Spray-Dried-Tablet Diluent

Magnesium Carbonate-Tablet Diluent

Maltodextrin-Tablet Diluent

Sodium Starch Glycolate-Tablet Disintegrant

Croscarmellose Sodium-Tablet Disintegrant

Crospovidone-Tablet Disintegrant

Magnesium Silicate-Tablet Glidant

Magnesium Trisilicate-Tablet Glidant

Talc-Tablet Glidant

Calcium Stearate-Tablet Lubricant

Starch, Sterilizable Maize-Tablet Lubricant

Sodium Stearyl Fumarate-Tablet Lubricant

Stearic Acid-Tablet Lubricant

Vegetable Oil, Hydrogenated-Tablet Lubricant

Zinc Stearate-Tablet Lubricant

Magnesium Stearate-Tablet Lubricant

Potassium Chloride-Tonicity Contributor

Sodium Chloride-Tonicity Contributor

Lauric Acid-Transdermal Penetration Enhancer

Linoleic Acid-Transdermal Penetration Enhancer

Myristic Acid-Transdermal Penetration Enhancer

Myristyl Alcohol-Transdermal Penetration Enhancer

Oleic Acid-Transdermal Penetration Enhancer

Tricaprylin-Transdermal Penetration Enhancer

Aluminum Monostearate-Viscosity Imparting For Oil

pharmaceutical excipients-boolket for pharmacy students

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