Review Article ISSN: 0974-6943

Md. Zaki Ahmad et al. / Journal of Pharmacy Research 2010, 3(9),2092-2095

Available online through www.jpronline.info Drug-excipient(s) interactions and compatibility study: A Review
Md. Zaki Ahmad*1,2, Vijay kumar, 1 Atul kumar 2, Sohail Akhter3 1 Dreamz College of Pharmacy, Sundernagar- Himachal Pardesh 2 Department of pharmaceutical Sciences, Dibrugarh University. Dibrugarh- Assam. 3 Faculty of Pharmacy, Jamia Hamdard, New Delhi

Received on: 15-04-2010; Revised on: 18-05-2010; Accepted on:13-07-2010 ABSTRACT

To facilitate the development of novel drug delivery systems, the demand of new excipients has been increased. Excipients is selected and used because it contributes one or more functional attributes to the product characteristics. The quality of medicines depends not only on the active principles and production processes, but also on the performance of the excipients. In earlier days, excipient(s) were considered inactive ingredients, but they may have tremendous effect on performance of active pharmaceutical ingredients in dosage form. The magnitude of this effect will depend upon physicochemical properties of drugs as well as quantity and quality of excipients used. The aim of this article is to identify the various processes/factors that cause the drug-excipients interaction and regulatory implication of drug-excipients interaction.

Key words: Excipients, active pharmaceutical ingredients, drug-excipients interaction, regulatory implication.
INTRODUCTION Pharmaceutical dosage form is a combination of active pharmaceutical ingredients (API) and excipients(s). When the total weight of any dosage form (solid, liquid (suspension, solution) is concerned then excipients(s) play a very important role. The ideal excipients(s) must be able to fulfill the important functions i.e. dose, stability and release of API from the formulation. Due to rapid evaluation of scientific, regulatory and economic, introduction of novel drug delivery systems, and advancement in biopharmaceuitcs, excipients(s) are now chosen to perform a variety of functions to insure the stability and bioavailability of drug substance in the formulation. Traditionally, excipients are regarded as inert and is expected that it should not interact with API and should not affect the quality safety and efficacy of dosage form [1- 3]. For the development of proposed pharmaceutical dosage form, three main components which should be consider are [4] a. Properties and limitation of API b. Properties and limitation of excipients c. Advantage and limitation of method(s) used In term of development of dosage form, all three considerations are of equally important. Excipients are the substance(s) other than API which are intentionally incorporated into pharmaceutical dosage form for specific purposes [ 5 ] such as a. Improvement of the stability of API in the dosage form b. Modulation of bioavailability of active pharmaceuticals ingredients c. Maintain the pH of liquid formulation d. Maintain the rheology of semisolid dosage form e. Act as tablet binders, tablet disintegrants, etc f. Act as antioxidant and emulsifying agents g. To allow the adequate administration h. To facilitate the manufacturing of dosage form i. For aesthetic reason j. For identification An excipients is selected and used as it should play one or more functional role in the final dosage form, therefore it is necessary to fully understand the function of an excipients, so as to characterize, understand and control the process as well as product quality, particularly in the new era of quality by design (QBD) [ 6 ]. Definition of excipients as developed by IPEC (International Pharmaceutical Excipients Council) America And IPEC Europe is, These are the substance(s) other than the API which has been appropriately evaluated for safety and is included in a drug delivery system to either aid processing of the system during manufacturing or protect, support or enhance stability, bioavailability or patients compliances or assist in product identification and enhance any other attributes of overall safety and effectiveness of drug product during storage or use [7, 8]. Excipients are considered to be inert in therapeutic or pharmacological action; they should inhibit unwanted phase transition and guarantee required stability of drug(s) in formulation during the production and storage period throughout the shelf life of product. Excipients are classified according to their functions [ 9 ] as: Binders Disintegrants Fillers (diluents) Lubricants Glidants Compression aids Colors Sweeteners Preservatives Flavors Film formers/coatings Suspending/dispersing agents/surfactants

The quality of the final product depends on the way in which the components are combined as it is on the components selected. In pharmaceutical dosage form API are in intimate contact with one or more excipients. Moreover in most of dosage form the quantity of excipients(s) are greater than the amount of API present in dosage form, for example typically a tablet contain binders, disintegrants, lubricants, and fillers [10], therefore excipients(s) can have tremendous impact on the performance of API when present in dosage form. It can influence the safety and effectiveness of drug depending upon route of administration, for example in solid dosage form excipients can affect safety and effectiveness by promoting or delaying gastrointestinal release. In one study it was reported that three out of ten formulation of phenylbutazone showed drugexcipients interaction in in-vitro study, where two of these formulation showed slow dissolution rate and low bioavailability, but third formulation showed slow rate of dissolution but bioavailability was approximately 100% [11]. Therefore, understanding of drug-excipients interactions is very important during selection of appropriate excipients(s) for proposed dosage form. To fulfill this purpose there is a need to carry out drug-excipients compatibility studies. There are various factors, which affect the drug-excipients stability; they are classified as [12] A. Drugs a. b. c. d. e. f. and excipients(s) factors Chemical properties Physical properties Critical moisture contents Impurity Size and/or surface area Appearance/morphological character

*Corresponding author.
Md. Zaki Ahmad Dreamz College of Pharmacy,Khilra-Meramesit,Sundernagar,Mandi (Himachal Pradesh),India Tel.: + 91-9805759952 Phone: 01905-248599, Fax: 01905-248600 E-mail:zaki.manipal@gmail.com

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B. Formulation factors a. Drug: excipients(s) ratio b. Mixing/milling of ingredients c. Granulation methods d. Packing arrangements e. Packaging C. Environmental factors a. Temperature b. Light c. Relative humidity Out of these all factors, drug-excipients interactions are of utmost important for a preformulation scientist during formulation development. Mechanism of drug-excipients(s) interaction Exact mechanism of drug excipients(s) interaction is not clear. However, there are several well documented mechanisms in the literature. Instability of drugs and/or excipients may be chemical like oxidation, hydrolysis or physical like polymorphism or crystallization. Due to certain excipients(s), significant physico-chemical change can occur in API like increase in rate of chemical degradation [13], formation of molecular complex, degree of crystallinity etc [14-16]. Drug-excipients(s) interaction occurs more frequently than excipient-excipient interaction [17-19]. Drug-excipients(s) interaction can either be beneficial or detrimental, which can be simply classified as [4] a. Physical b. Chemical c. Biopharmaceutical Physical interaction It is quite common, but is very difficult to detect. Physical interaction doesnt involve any chemical changes. Physical interactions are frequently used in manufacturing of dosage form, for example to modify drug dissolution (example in solid dispersion). However many of the physical interaction are unintended which usually causes the problems. Different physical interactions are as follows: Solid dispersion In one study Desai et al found that solid state interaction occurred between povidone and stearic acid resulted in formation of solid dispersion at the storage temperature of 40 C/23% RH and above in capsule formulation containing both povidone and stearic acid [20], which result in slow dissolution of drug most possibly because of such interaction. Complexation Complexing agents usually bind reversible with drugs to form complex, which do not allow them to dissolve, complexing agent such as cyclodextrin are often used to increase the bioavailability of poorly water soluble drugs [21-25]. However, it was found that complexation of cyclodextrin with non-steroidal anti-inflammatory drug (NSAID) naproxen [26] and tolbutamide [27] increased the dissolution, but there was no corresponding increase in bioavailability. In one study it was observed that tetracycline formed insoluble complex with calcium carbonate, which lead to slower dissolution and decreased absorption. Similarly, phenobarbital formed an insoluble complex with PEG-400, which resulted in slower dissolution and decreased absorption [28]. In-vitro evaluation of complexation of steroids prednisolone with water soluble excipients(s), showed increased dissolution, but the complexes were having high molecular weight and might be too large to diffuse through GI membrane, therefore it may be possible that in-vivo bioavailability of prednisolone would be lower [29]. Similarly formulation of chlorpromazine with polysorbate 80 and sodium lauryl sulfate decreased the membrane permeability of drugs, because of low Critical Micelle Concentration (CMC) of polysorbate 80, which resulted in formation of soluble micellar aggregates, but in case of sodium lauryl sulfate which is having high CMC, formed insoluble complex between lauryl sulfate anion and chlorpromazine cations [30]. Adsorption Adsorption of drug molecules onto the surface of excipients(s) can render the drug unavailable for dissolution and diffusion, which can result in reduced bioavailability. For example, antibacterial activity of cetylpyridinium chloride was decreased when magnesium stearate was used as lubricants in tablet containing cetylpyridinium chloride; this was due to adsorption of cetylpyridinium cation by stearate anion on magnesium stearate particle [31]. In one of the investigation, it was observed that dissolution of drug was decreased due to adsorption of drug on the surface of microcrystalline cellulose [32]. Chemical Interaction Chemical interaction involves chemical reaction between drugs and excipients to form different molecule(s).Chemical interactions are almost detrimental to the product because they produce degradation products,different degradation product are classified as in ICH guideline ICHQ3B[33]. Different types of chemical drug-excipients(s) interaction have been reported in the literature. For example primary amine group of chlorpromazine undergoes Maillard reaction with glycosidic hydroxyl group of reducing sugar dextrose to form imine,which finally breakdown to form Amidori compounds[34]. In one another study it was observed that release of diclofenac sodium from matrix tablet was inhibited by polymer chitosan at low pH, most possibly via formation of ionic complex between diclofenac sodium and ionized cationic polymer[35]. In one vitamin formulation it was investigated that decomposition of ascorbic acid was increased when silica gel was added, which may be due to the presence of trace metals like iron and/or copper, which catalyses the decomposition of ascorbic acid in the solution[36]. Forni et al reported that interaction between chloramphenicol stearate and colloidal silica during grinding leads to polymorphic transformation of drugs[37]. Dextrose is widely used as tonicity modifier in the parenterals dosage form and it is used as nutrition solution. Sterilizations by autoclaving of such parenteral preparations containing dextrose can cause isomerization of dextrose in fructose and formation of aldehyde (5-hydroxymethyl furfuraldehyde), which can react with primary amino group to form shiff base and colour development[38]. Wirth et al showed that Maillard reaction product was also found in capsule containing lactose and antidepressant Fluoxetine[39]. Process affected by drug-excipients interaction In solid dosage form, most drug-excipients interaction whether physical or chemical can affect the processes like disintegration and dissolution; however other processes such as pH of the microenvironment, permeability through gastrointestinal membrane can also alter the bioavailability of API in the formulation. In vitro disintegration test is official in almost all Pharmacopoeias. This test determines whether tablets or capsule disintegrate within a prescribed time when placed in a liquid medium under the given experimental condition. It is defined as state in which no residue of the tablet or capsule remain on the screen of apparatus or if residue remain it consist of fragment of insoluble coating of tablet or capsule shells or is a soft mass with no palpable core [40]. If drug-excipients interaction attributes to more rapid disintegration, then absorption will increase. For example increased dissolution was observed with antidiabetic drug tolbutamide, when it was spray dried in combination with partly pregelatinized cornstarch as disintegrants [41]. In another study, it was reported that super-disintegrant sodium starch glycolate increased the bioavailability of furosemide significantly in comparison to other disintegrants [42]. Bioavailability of the drug will reduce, if disintegration is rate-limiting step in absorption, and drug-excipients interaction results in very slow disintegration of a drug. For example in vitro disintegration test of six commercial formulation of praziquantal showed that one formulation failed to disintegration test in water and acidic media; also, its in vivo bioavailability was lower than other formulation [43]. In addition decrease in disintegration and dissolution was observed when antibacterial sulphanilamide was formulated with sodium starch glycolate, Veegum, Amberlite as disintegrating agents [44]. Therefore, there is a requirement for quantitation, identification and ultimately qualification of drug excipients(s) interaction for safety assessment. Compatibility study Drug-excipients compatibility study Compatibility study is the most important part of any pre-formulation testing of proposed dosage form, and it is necessary that it should be carried out before the development of first formulation of proposed dosage form with a new drug or new formulation of existing API[45]. This is required due to the following reasons: Formulation stability studies are time consuming and expensive Need to minimize the number of model formulations Provide rational basis for selecting excipients used in model formulations Goal of drug-excipients compatibility study: These are as follow i. To find out the excipients that are incompatible with the API ii. To find out that excipients do not have any impact on the stability of the API iii. To find out the excipients that can stabilize the unstable API iv. To assign a relative risk level to each excipients within a functional v. To design and develop selective and stability-indicating analytical methods to determine the impurities, wherein the dosage strength difference is very large Due to presence of more than one API in fixed-dose combinations (FDC), chemical and physical stability of API may become very complicated. Not only API may react with each other to form degradation products but also APIs may react with excipients, which are otherwise compatible with one of single API. These attributes create many problems for product development and analysis of FDC. Strategic design in drug-drug and drug excipients compatibility studies and development of appropriate analytical method, which is able to detect all potential impurities, and degradant, are very important in successfully developing a stable FDC. The main objective behind the compatibility testing is to find out most appropriate excipients(s) for the particular API in dosage form under consideration and also those excipients(s) that should be avoided for particular API, and to ascertain appropriate excipients(s) which may be reasonably used with drugs in proposed dosage form so that process control and hence product quality should not be compromised. As suggested by Carstensen et al [45], for tablet formulation, the ratio of drug-excipients(s) should be 20:1 and 1:5 by weight for lubricants and other excipients(s) respectively. Indomethacin exhibit different polymorphism, and different forms have different solubility and it may have different bioavailability. Polymorphic and thermodynamic

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study of different polymorphs was carried out by Legendere and Feutelais using DSC (differential scanning calorimetry), TG (thermo gravimetric analysis) and X-ray diffraction and thermomicroscopy [46]. They reported that form I is stable at atmospheric pressure, while form II is metastable. This existence of metastable form of indomethacin at room temperature and atmospheric pressure may attribute difficulties in formulation of cream, ointments, and suspension. Drug-excipients compatibility studies by physico-chemical techniques using indomethacin was carried out by Marini et al [47], where they used the physico-chemical properties of drug and different combination with several excipients [magnesium stearate, polyvinylpyrrolidine (PVP), and Avicel]. Properties of pure compounds both untreated and moisture/temperature treated was compared with binary mixture of drug-excipients (treated with same condition). In this study they reported that indomethacin doesnt interact with PVP and magnesium stearate, but is compatible with Avicel [47]. In one of the study color change of rapeprazole-excipients mixture were measured by using spectrocolorimeter, it was reported that relationships of the percentage of decomposed drug contents versus the color change value, and percentage of drug degradation product versus color changes value were exponentially increased in formulation containing zinc stearate, as the degradation of rabeprazole can be greatly influenced in stress condition such as humidity as well as temperature [48]. In one of the study it was reported that both qualitative and quantitative interaction indicator were identified, when compatibility between tricyclic - lacatam antibiotic and commonly used excipients such as polyvinylpyrrolidone, magnesium sterate and lactose (drug:excipients ratio 80:20 and 20: 80 (w/w)) were analyzed by using number of experimental techniques (TG-DSC, FT-IR, X-ray powder diffraction, SEM) [49]. Macedo et al (2001) reported the chemical interaction between hydrochlorothiazide-lactose mixture and generic hydrochlorothiazide formulation due to Maillard reaction between the hydrochlorothiazide and lactose present in the formulation during the compatibility and stability study of some binary mixture and generic hydrochlorothiazide formulation [50]. DSC-photovisual data revealed the thermal decomposition with changes in color. A physical interaction was observed between hydrochlorothiazide and lactose in binary mixture, whereas high compatibility was observed between drugs and microcrystalline cellulose (101). Compatibility and stability studies of proparanolol binary mixtures (propranolol hydrochloride-18.60%, microcel 101-32.56%, lactose -13.95%, starch -27.91%, PVP - 3.26%, talc -2.32% and magnesium stearate - 1.40%), and two tablet were studied by Macedo et al (2002) and compared by using thermogravimetric (TG), and DSC method. TG isothermal study shows the difference in the profile between drug and tablets due to excipients quality and problem in manufacturing problem. DSC of the binary mixture shows that similar phase transition to propranolol drug where as phase transition of tablet was decreased no any interaction was observed in propranolollactose mixture [51]. However, Maillard reaction was observed by DSC-photovisual test. Thermal decomposition behavior of ascorbic acid was influenced by presence of dibasic calcium phosphate, microcrystalline cellulose, stearic acid magnesium stearate, and silicon dioxide excipients in vitamin C tablet formulation, when thermal decomposition of ascorbic acid and its excipients was studied in nitrogen atmosphere using thermogravimetric balance. In this study it was observed that only microcrystalline cellulose was not affected by presence of calcium phosphate, stearic acid or silicon dioxide [52]. Drug-Excipients compatibility study of atenolol was carried out by Marini et al in presence of several excipients [polyvinylpyrollodine (PVP), Magnesium stearate, Avicel ]. Drug excipients mixture were exposed to moisture, they reported that Avicel has no interaction with atenolol but magnesium stearate showed significant thermal response, while PVP interact strongly with atenolol, which may be mediated via hydration of water presence in excipients [53]. Piroxicam-excipients (chitosan and cellulose) compatibility study was conducted by Drebushchak et al by using DSC. They reported that both excipients interact with drug, which result in 0 decrease of melting point by 8 C and enthalpy was reduced by twice, chitosan increases its solubility by 10 times [54]. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used as antihypertensive agent. Compatibility studies between captopril and pharmaceutical excipients used in tablet formulation was investigated by Stulzer et al [55] by using DSC, thermogravimetric (TG), X-ray powder diffraction and FTIR, they reported the possible drug-excipients interaction with magnesium stearate by DSC technique. Mura et al reported the some drug excipients interaction of ibuproxam with polyethyleneglycol 4000, palmitic acid, and stearic acid, calcium and magnesium stearate using DSC, hot stage microscope and scanning electron microscopy [56]. Compatibility study of isosorbide mononitrate with selected excipients was carried out by Rajan K. Vermal and S.garg by using DSC and isothermal testing(IST). Based upon the investigation they reported that cellulose acetate and microcrystalline cellulose shows interaction with isosorbide mononitrate. Result of IST showed that incompatibility between isosorbide mononitrate and cellulose acetate [57]. Lapachol is a naphhthoquinone derivatives having antimicrobial and anticancer activity. Compatibility study of binary mixture of lapachol was carried out in preformulation study of lapachol gel-cream formulation. In the study it was reported that lapachol shows interaction in binary mixture of lapachol methylparaben, lapacholcetostylalcohol and lapachol-gycerol monostearate which influences the stability of product [58]. Mura et al reported that the drug-excipients interaction of ketoprofen with palmitic acid, stearic acid and steryl alcohol and eutectic formation was observed with stearate. Solid-solid phase interaction with polyethylene glycol 6000, and polyvinylpolyrrolidone and polyvinylpyrrolidone K30 was observed [59]. Sugar is widely used pharmaceutical excipients in solid and liquid dosage form, and because of their hydrophilic nature they can strongly interact with moisture [60]. For example in one of the study it was reported that -lactose monohydrate could accelerate the hydrates formation of API in formulation during storage at 95% RH at 40C [61]. Thus, active principle of medicine are not only responsible for quality of medicine but this is also depends upon performance of excipients(s) used in formulation of dosage form. Therefore, there is requirement to develop a scientifically and comprehensive excipients qualification program to ensure the purity, safety, efficacy, suitability and characterization of excipients. Safety assessment of pharmaceutical excipients In the beginning there was no any regulatory agency to guideline which can specifically address the toxological testing of a material intended for use as excipients in pharmaceutical preparations. In recent years the U.S. Food and drug administration (FDA) has shown significant amount in interest and efforts in defining, reviews and permitting use of excipients as part of the new drug application (NDA) process (U.S. Federal Food, Drug and Cosmetics act, 1990) [62]. The drug master file for excipients is reviewed only as part of NDA process. The international Pharmaceutical excipients council (IPEC) was formed in 1991 to address prevalent industry concerns related to the international harmonization of excipients standard, the introduction of new excipients in market and development of safety evaluation of guideline for excipients. The guideline for safety assessment of pharmaceutical excipients was developed by Safety Committee of the International pharmaceutical excipients council, which represent a new, scientifically based approach to establish condition for the safe use of proposed pharmaceutical excipients utilizing various route of human exposure. These guidelines are based upon the best available toxological data and International Conference on Harmonization (ICH) [63-67]. These guideline were developed with reference to FDA implantation documents (Proposed implantation of international conference on harmonization consensus regarding new drug application) (U.S FDA, 1992) and other international guidance documents (World Health Organization, 1987; Organization for Economic Operation and Development, 1987) [68-70]. Conclusions The quality of medicines depends not only on the active principles and manufacturing process but this also depend upon performance of excipients. The concept of excipients from an inert cheap vehicle has changed to an essential constituent of the formulation. Excipients(s) are needed not only for the dosage form necessities, but also to perform important and specific technological functions, especially in case of dosage form. Optimizing the selection of excipients in the formulation can reduce drug-excipients incompatibility during production and storage period of dosage form. 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Journal of Pharmacy Research Vol.3.Issue 9.September 2010

2092-2095