environmental friendly pharmaceutical excipients towards green manufacturing

8/3/2019 Environmental Friendly Pharmaceutical Excipients Towards Green Manufacturing

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ENVIRONMENTAL FRIENDLY PHARMACEUTICAL EXCIPIENTS TOWARDS

GREEN MANUFACTURING

Seema Pushkar 1*, Nikhil K Sachan1, S.K. Ghosh2

1University Institute of Pharmacy, C.S.J.M. University, Kanpur-208024 U.P. India

2Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh- 786004 Assam, India

ABSTRACT

Drugs are rarely administered as pure chemical substances alone and are almost always given

as formulated preparations or medicines. Drug dosage forms contain many components inaddition to the active pharmaceutical ingredient(s) to assist in the manufacturing process as

well as to optimize drug delivery. Nature has provided us a wide variety of materials to helpimprove and sustain the health of all living things either directly or indirectly. In recent years

there have been important developments in different dosage forms for existing and newly

designed drugs and natural products, and semi-synthetic as well as synthetic excipients oftenneed to be used for a variety of purposes. The components employed as excipients must

present the characteristics required by their technological function but, as with any substance

administered to man, they must also correspond to suitable safety requirements. Since

pharmaceutical natural excipients may be comply with many requirements such as non-

toxicity, stability, availability and renewability they are extensively investigated for use in the

development of solid oral dosage forms.

KEYWORDS: Pharmaceutical excipients, Natural excipients, Green pharmacy



OVERVIEW OF PHARMACEUTICAL EXCIPIENTS

The International Pharmaceutical Excipients Council (IPEC, www.ipec.gov) defines anexcipient as any substance other than the active drug or prodrug that is included in the

manufacturing process or is contained in a finished pharmaceutical dosage form (1). Today'scommercially available excipients provide a gamut of required functions, from processing

aids that increase lubricity, enhance flowability, and improve compressibility andcompatibility to agents that impart a specific functional property to the final product (e.g.,

modifying drug release). The US Pharmacopeia±National Formulary (USP±NF ) categorizes

excipients as binders, disintegrants, diluents, lubricants, glidants, emulsifying±solubilizing

agents, sweetening agents, coating agents, antimicrobial preservatives, and so forth. In

addition to their functional performance, ideally, excipients should be chemically stable,

nonreactive with the drug and other excipients, inert in the human body, have low equipment

and process sensitivity, have pleasing organoleptic properties, and be well characterized and

well accepted by the industry and regulatory agencies. A limited choice of excipients with all

of these attributes and presently available in the market can make formulation design and

excipient selection challenging.

Excipients are categorized as compendial or noncompendial materials. Compendialexcipients have composition consistent with monographs published in compendia such as

USP±NF. Generally speaking, compendial excipients are the better characterized excipientsand most likely to possess the desirable qualities previously stated. These materials are

recognized as preferred excipients for pharmaceutical formulations. Noncompendialexcipients might also be applied in pharmaceutical formulations. The use of these

noncompendial materials is supported by Type IV drug master files (DMFs) in regulatorydossiers (i.e., new drug applications, abbreviated new drug applications, and investigational

new drug applications). These files are maintained by excipient manufacturers with theagency and support the safety of the excipient as well as the quality and consistency of

excipient manufacturing.

There may be approved drug products containing noncompendial excipients, thereby

demonstrating the acceptance of these excipients by the US Food and Drug Administration or other agencies in the major markets. For materials in which toxicity is a possible concern,

formulators can gain information about the excipient's regulatory acceptance and allowableamount by consulting with excipient manufacturers and toxicology experts. This information

also may be found in the Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide (2), and other references. In addition, 21 CFR parts 182 and 184

list generally regarded as safe (GRAS) food ingredients.

PHARMACEUTICAL DEVELOPMENT:

For lifecycle management, improved formulations replace or are marketed with alreadyavailable products. By setting up an excipient formulary, which includes a sufficient number of carefully selected excipients and links to various unit processes, efforts can be geared

toward a better understanding of excipients, functionality-test development, vendor relationships (e.g., vendor qualification), and second-vendor identification and

qualification.The establishment of an excipient formulary can lead to more efficient use of available assets, decreased development times, harmonized specifications, worldwide

formulation acceptance, and economy in product manufacturing.



Excipient selection in the drug product±development phase focuses on the desirablecharacteristics (e.g., functionality, material consistency, regulatory acceptance, cost,

availability, and sources). Ingredients derived from natural animal sources (e.g., gelatin,starch) have raised concerns of transmissible spongiform encephalopathy/bovine spongiform

encephalopathy/genetically modified organism (TSE/BSE/GMO). A verification letter from a

vendor of these natural materials is sufficient to support non-GMO or TSE/BSE implication

for consumer protection. Some vendors also provide prionics-check certification for ingredients from animal sources.

Imprudent selection of excipients and excipient vendors may lead to process-development

problems (see sidebar "Potential problems related to excipients").

Excipient and vendor selections can greatly influence development time, performance,

quality, and acceptance of final products. Consequently, quality excipient suppliers should:

y maintain drug master files with FDA for noncompendial items;

y consistently conform to monograph requirements;

y manufacture in ISO 9000±certified facilities;

y pass FDA inspection and auditing by either pharmaceutical companies or International Pharmaceutical Excipient Audit (IPEA, www.ipeainc.com).

Inattention to excipients, excipient suppliers, and regulations may lead to product

development failure. Quality-by-design concepts, which have recently been initiated by FDA,

emphasize the need for characterizing material properties (e.g., micromeritic, chemical,

thermal, rheological, and mechanical properties) and elucidate their vital role in formulation

and manufacturing processes (3-6).

NEW EXCIPIENTS:

Currently available excipients are sufficient to support typical formulationdevelopment. A significant number of drug entities under development, however, have

physicochemical, permeation, and pharmacokinetic properties that are less than ideal. These

drugs present formulation challenges and may require either the discovery of new excipients

or new applications of existing excipients. Regulatory agencies require new excipients to

undergo a series of toxicology tests, which may be costly.

Few new excipients of new chemical entity have been introduced into the market,

primarily because of the economic hurdles associated with toxicology testing. Instead,

excipient manufacturers have improved excipient performance and have expanded product

lines by modifying already approved products (see Table I). Excipients undergoing these

approaches may be advantageous in their formulation, manufacture, and marketing. In

formulation, these excipients may decrease strain rate sensitivity, increase rework potential,increase dilution potential, decrease lubricant sensitivity, enhance flow properties, enhance

the blending process, optimize content uniformity, increase compression ratio, facilitate

material handling, require smaller quantities, decrease environmental concerns, and improvestability. These formulation benefits can lead to manufacturing advantages such as enable

direct compaction to avoid time-consuming wet granulation, increase production capacityusing excipients with enhanced flow and compaction behavior, reduce tablet tooling and

machine wear, and eliminate the facility need of solvent recovery. Benefits such as rapid



formulation development, smaller tablet size, better quality products, and no solvent residuesmay be possible by using these excipients with proven functionality.

Many APIs under development have less than ideal physicochemical and absorption

properties, resulting in poor bioavailability. Excipient manufacturers have developedenabling excipients such as various solubilizers and absoption enhancers for these hard-to-

deliver compounds.

Table 1: Natural Products, including naturally occurring polymers and derivatives

Name Use

DRUG DELIVERY:

Drug delivery is highly innovative in terms of materials to assist delivery, excipients,

and technology which allow fast or slow release of drugs. For example analgesics, whichoften involve as much as five or six tablets a day, can be reduced to a single dose by usingappropriate excipients, based on carbohydrate polymers. Polymers are classified in several

ways; the simplest classification used for pharmaceutical purposes is into natural and

synthetic polymers. Polysaccharides, natural polymers, fabricated into hydrophilic matrices

remain popular biomaterials for controlled-release dosage forms and uses of a hydrophilic

polymer matrix is one of the most popular approaches in formulating an extended-release

dosage forms (7-9). This is due to the fact that these formulations are relatively flexible and a

well designed system usually gives reproducible release profiles. Since drug release is the



process by which a drug leaves a drug product and is subjected to absorption, distribution,metabolism, and excretion (ADME), eventually becoming available for pharmacologic

action, hence drug release is described in several ways as follows:a) Immediate release refers to the instantaneous availability of drug for absorption or

pharmacologic action in which drug products allow drugs to dissolve with no intention of

delaying or prolonging dissolution or absorption of the drug.

b) Modified-release dosage forms include both delayed and extended-release drug products.Delayed release is defined as the release of a drug at a time other than immediately following

administration, while extended release products are formulated to make the drug available

over an extended period after administration.

c) Controlled release includes extended-release and pulsatile-release products. Pulsatile

release involves the release of finite amounts (or pulses) of drug at distinct intervals that are

programmed into the drug product.

One of the most commonly used methods of modulating tablet drug release is to

include it in a matrix system. The classification of matrix systems is based on matrix

structure, release kinetics, controlled release properties (diffusion, erosion, swelling), and the

chemical nature and properties of employed materials. Matrix systems are usually classifiedin three main groups: hydrophilic, inert, and lipidic (10). In addition, the drug release is a

function of many factors, including the chemical nature of the membrane, geometry and itsthickness, and the particle surface area of the drug device, the physico-chemical nature of the

active substance and the interaction between the membrane and the permeating fluids are alsoimportant (11-13). In fact, the mechanism probably varies from membrane to membrane,

depending on the membrane structure as well as on the nature of the permeating solution. It is believed that several different mechanisms are involved in the drug release through a non

disintegrating polymer coat (14):

a) Permeation through water-filled pores; in this mechanistic model, the release of the drug

involves transfer of the dissolved molecule through water-filled pores. The coating membrane

is not homogeneous. The pores can be created by the incorporation of leachable components,

such as sugars or incompatible water soluble polymers into the original coating material (15)

or can be produced by an appropriate production process.

b) Permeation through membrane material; in this mechanism, the release process involves

the consecutive process of drug partition between the core formulation and the membrane.

The drug molecules are dissolved in the membrane at the inner face of the coat, representing

equilibrium between a saturated drug solution and the membrane material. The transport of

drug across the coat is then driven by the concentration gradient in the membrane. Outside

the membrane, the drug is dissolved in an aqueous environment.

c) Osmotic pumping; this release mechanism is driven by a difference in osmotic pressure between the drug solution and the environment outside the formulation. In addition to the

above, controlled release of drug from the matrix is dependent on particle size and type of the polymer wetting, polymer hydration, polymer dissolution, and drug: polymer ratio (16± 19).

The hydration rate depends on the nature of the constituents, such as the molecular

structure and the degree of substitution. The viscosity of the aqueous solution can beincreased by increasing the average molecular weight of the polymer, the concentration of the polymer or decreasing the temperature of the solution [7, 20]. So, the factors associated with

polymers, such as molecular weight type (nominal viscosity), concentration, degree of

substitution, and particle size [21±28]; have been shown to have a significant influence on

drug release. For example, in tablet formulations containing hydrophilic polymers like

HPMC, the release of active drug is controlled by the rate of formation of a partially hydrated

gel layer of the tablet surface formed upon contact with aqueous gastric media following

ingestion and the continuous formation of additional gel layers. In addition to this, process



variables like method of granulation, amount of binder added during granulation, use of highor low shear mixer, granule size distribution, compression force during tableting, etc., are

also important for extended-release [29-39].

POLYSACCHARIDES IN PHARMACEUTICALS:

Natural polysaccharides are extensively used for solid form formulations. They are highlystable, safe, nontoxic, and hydrophilic and gel forming in nature. Pectin, starch, guar gum,

amylase and karaya gums are a few polysaccharides commonly used in dosage forms. Non-

starch, linear polysaccharides remain intact in the physiological environment of the stomach

and the small intestine,but are degraded by the bacteria present in human colon which make

them potentially useful in targeted drug delivery systems to the colon (40).

a) Pectins:

Pectin are non-starch.linear polysaccharides extracted from plant cell walls. They are

predominantly linear polymers of mainly linked D-galacturonic acid resides interrupted by1,2-linked L-rhamnose residues with a few hundred to about one thousand building blocks

per molecule, corresponding to an average molecular weight of about 50,000 to about1,80,000 Being soluble in water, pectin is not able to shield its drug load effect effectively

during its passage through the stomach and small intestine. It was found that a coat of considerable thickness was required to protect the drug core in simulated in vivo conditions.

Mixed films of pectin with ethylcellulose were investigated as a coating material for colon-specific drug delivery. Sungthongjeen et al investigated the high-methoxy pectin for its

potential value in controlled-release matrix formulations (41). The effects of compression

force,ratio of drug to pectin, and type of pectin on drug release from matrix tablets were also

investigated. A very low solubility pectin-derivative (pectinic acid, degree of methoxylation

4%) was found to be well suited as an excipient for pelletisation by extrusion/spheronisation.

Pectin microspheres of piroxicam were prepared by the spray dying technique. In vivo tests

in rabbits with dispersions of piroxicam-loaded microspheres also indicated a significant

improvement of piroxicam bioavailbility in the aqueoushumuor (2.5-fold) when compared

with commercial piroxicam eye drops (42).

b) Alginates:

Alginates are natural polysaccharide polymers isolated from the brown sea weed

(Phaeophyceae). Alginic acid can be converted into its salts, of which sodium alginate is themajor form currently used. A linear polymer consisting of D-mannuronic acid and L-

guluronic acid residues arranged in blocks in the polymer chain, these homogenous blocks(composed of either acid residue alone) are separated by blocks made of random or

alternating units of mannuronic and guluronic acids. Alginates offer various applications in

drug delivery, such as in matrix type alginate gel beads, in liposomes, in modulatinggastrointestinal transit time, for local applications and to deliver the bio molecules in tissueengineering application[43].

c) Starches:

It is the principal form of carbohydrate reserve in green plants and especially present in

seeds and underground plant organs. Starch occurs in the form of granules (starch grains), the

shape and size of which are characteristic of the species, as it is also the ratio of the content of



principal constituents, amylase andamylopectin. A number of starches are recognized for pharmaceutical use. These include maize( Z eamays),rice(Oryza sativa),wheat(Triticum

aestivum) and potato(Solanum tuberosum) (44). Modified starch was tested for generalapplicability of a new pregelatinized starch product in directly compressible controlled-

release matrix systems.It was prepared by enzymatic degradation of potato starch followed by

precipitation (retrogradation), filtration and washing with ethanol. The advantages of the

material include ease of tablet preparation, the potential of a constant release rate(zero- order)for an extended period of time and its ability to incorporate high percentages of drugs with

different physicochemical properties (45). Acetylating of starch considerably decreases its

swelling and enzymatic degradation. Thus, starch acetate (SA) based delivery systems were

tested for controlled drug delivery (46).

B. GUMS:

a) Gum:

Gums are considered to be pathological products formed following injury to the plant or owing to unfavourable conditions, such as drought, by a breakdown of cell walls (extra

cellular formation; gummosis). Gums are pathological products(47). Acacia, tragacanth, andguar gum are examples of gums. Gums are plant hydrocolloids. They are also translucent

amorphous substances and polymers of a monosaccharide or mixed monosaccharides andmany of them are combined with uronic acids. Gums constituents and on hydrolysis yield a

mixture of sugars and uronic acids. Gums and hydrophilic molecules, which can combinewith water to form viscous solutions or gels. The nature of the compounds involved

influences the properties of different gums. Linear polysaccharides occupy more space and

are more viscous than highly branched compounds

of the same molecular weight. The branched compounds form gels more easily and are more

stable because extensive interaction along the chains is not possible.

a) Gellan gum:

Deacylated Gellan gum (Gellan) is an anionic microbial polysaccharide, secreted from

Sphingomonas elodea, consisting of repeating tetrasaccharide units of glucose, glucuronic

acid and rhamnose residues in a 2:1:1 ratio: [3)±±D±glucose±(14)±±D±glucuronic acid±

(14)±±D± glucose±(14)± ±L±rhamnose±(1]. In the native polymer two acyl

substituents, L-glyceryl at O(2) and acetyl at O(6), are present on the 3-linked glucose. On

average, there is one glyceryl per repeating unit and one acetyl for every two repeating units.Deacylated Gellan gum is obtained by alkali treatment of the native polysaccharide. Both

native and deacylated Gellan gum are capable of physical gelation (48). To induce Gellangelation it is necessary to warm up preliminarily a concentrated water solution of the

polysaccharide: when the temperature is decreased, the chains undergo a conformationaltransition from random coils to double helices (Coil-Helix Transition). Then a rearrangement

of the double helices occurs leading to the formation of ordered junction zones (Sol-Gel

Transition) (49) thus giving a thermo-reversible hydrogel (50). Much stronger physical

thermo-reversible hydrogels are also obtained by addition of mono and divalent ions to

Gellan solutions or in acidic conditions (51). The physical gelation properties make this

polysaccharide suitable as a structuring and gelling agent.



C. VOLATILE OILS:

a) Methanol:Methanol is obtained by steam distillation of the flowering tops of Mentha piperita

belonging to the family Labiatae. A membrane- moderated transdermal therapeutic

system(TTS)of nimodipine using 2%w/w hydroxypropylmethylcellulose (HPMC) gel as a

reservoir system containing menthol as penetration enhancer and 60%v/v ethanol- water assolvent system (52). Methanol was tested for improving the bioavailability of poorly water-

soluble ibuprofen in the rectum with poloxamer (52,53).

b) Caraway:

Caraway fruit consists of the dried, ripe fruits of Carum carvi (Umbelliferae).The volatile

oil consists of ketone carvone and the terpene limonene. In another attempt, a limonene-

based transdermal therapeutic system (TTS) was prepared to study its ability to provide the

desiredsteady-state plasma concentration of nicorandil in human volunteers (54).

DRUG±EXCIPIENT AND EXCIPIENT±EXCIPIENT INTERACTIONS:

Interactions between drugs and excipients can occur by means of several possible

mechanisms, including adsorption, complexation, chemical interaction, pH effects, andeutectic formation, resulting in drug products with desired or undesired properties.

Water-insoluble cellulose-type excipients such as microcrystalline cellulose and

croscarmellose sodium can adsorb APIs during wet granulation or in dissolution testing,

thereby leading to incomplete dissolution. This incomplete dissolution, however, usually is

not present at an alarmingly high level when only van der Waals forces are operative.

Substantial electrostatic interactions can occur between oppositely charged excipients and

drugs, for example. Negatively charged excipients may not be compatible with positively

charged drugs or excipients and positively charged excipients can interact with negativelycharged drugs and excipients. Based on the Henderson-Hasselbalch equation, alkalinizing

agents (e.g., sodium bicarbonate, calcium carbonate, magnesium oxide) and acidifiers (e.g., citric acid, tartaric acid, malic acid, fumaric acid) can influence the microenvironment pH

significantly and may have a major influence on drug solubility or dissolution for acidic and basic drugs. Drug±excipient interaction examples have been reviewed (55).

Furthermore, formulation scientists should evaluate the possibility of excipient±excipient

interactions and their influence on drug-product attributes. An excipient±excipient interactionsometimes can be used as a formulation strategy to achieve desired product attributes. For

example, the viscosity of xanthan gum is increased in the presence of ceratonia (56), and the

viscosity of non-ionic cellulose derivatives (hydroxypropyl methylcellulose and

hydroxypropyl cellulose) is enhanced by the incorporation of sodium lauryl sulfate (57).These excipient±excipient interactions are used synergistically in controlled-release drug

delivery systems.



CONCLUSION:

In addition to conventional pharmaceutical excipients as bulking agents, substanceuse for masking taste/texture or as a substance use to aid during manufacturing process,

Novel excipients offer broad range of additional properties suitable to preserve the integrity

of active constituents of the formulation and enhances it¶s self life. New and modified

excipients, irrespective of its source (synthetic or herbal) produces formulation that offer better drug delivery performance, reliability, negligible toxicity, enhances stability, improve

bioavailability and patient acceptability. It also avoids dependence of pharmaceutical industry

on rapidly perishing non renewable resources like fossil fuel. The synthetic polymers can be

designed or modified as per requirement of the formulation; by altering polymer

characteristics and on the other hand herbal pharmaceutical excipients are biocompatible, non

toxic, environment friendly and economical. It seems conceivable that in the near future,

kilogram quantities of fusion proteins, fibronectin, poly (lysine), or hemolysin could become

available as off-the-shelf excipients or as designer excipient kits. This scenario is even more

plausible considering that moieties that were unheard of a decade ago are now routinely

available for use as excipients or in biochemical research (e.g., Lipofectamine, poly (lactide-co-glycolide), PAMAM dendrimers, tocopherol PEG succinate, etc.). Excipients that have

never been used before must pass formidable regulatory requirements before beingincorporated into approved dosage forms. Such requirements include, but are not limited to,

comprehensive toxicology (including acute, chronic, and reproductive) and pharmacokineticand carcinogenic studies as outlined in the ICH S7, S3A, S3B, S2B, and S5A and the US

Pharmacopeia

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environmental friendly pharmaceutical excipients towards green manufacturing

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