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Drugexcipient interactions and their affect on absorption

Kimberley Jackson, David Young and Sonia Pant
Excipient(s) are traditionally thought of as inert but they can have a tremendous impact on the ultimate pharmacological availability of a drug substance when added to a formulation. The magnitude of this effect will depend on the characteristics of the drug and on the quantity and properties of the excipients. The aim of this article is to identify the various physicochemical and physiological processes that can be altered by drugexcipient interactions and to explore mechanisms by which they might occur. The regulatory implications of drugexcipient interactions will also be discussed. large proportion by weight of a formulated product when, for example, the active ingredient is very potent1. (The physical characteristics of the diluent are important; for example, triamterene was shown to dissolve more rapidly when it was formulated with hydrophilic fillers such as lactose and starch as compared with insoluble diluents2). Disintegrants tend to swell when wetted and so are added to a formulation to facilitate the breakdown of the dosage form into granules and powder particles3,4.The newer disintegrants, called superdisintegrants, cause an extremely rapid breakup of a tablet owing to their ability to swell to many times their original size57. Binders provide cohesiveness to a powder mixture to ensure that a tablet formulation will be compressible and remain intact throughout its shelf-life yet will still disintegrate in vivo. Disintegration and dissolution times can be optimized by varying the concentration of binders in a formulation8,9. Lubricants tend to be hydrophobic substances that act by coating particles to prevent adhesion of the tablet to the dies and punches of the tableting machine, to aid in ejection of the tablet from the die by reducing the interparticulate friction and improving flow of the powder mixture4,10. Very small quantities are often used (1% or less of the formulation) because too much lubricant can waterproof the tablet, which can hinder its disintegration, dissolution and/or bioavailability1,2,11,12. Processes affected by drugexcipient interactions After oral administration of a drug in tablet form, the solid formulation will disintegrate and, although dissolution can occur directly at the surface of an intact tablet, a rapid rate of dissolution will typically occur as the tablet is fragmented. In most cases, the drug in solution is then absorbed by passive diffusion into the

Kimberley Jackson, David Young* and Sonia Pant GloboMax LLC 7250 Parkway Drive Suite 430 Hanover MD 21076 USA *tel: 1 410 712 9500 fax: 1 410 712 0737 e-mail: info@globomax.com

w Most drugs intended for oral administration

require formulation with excipients to allow for adequate administration, to facilitate manufacturing of the product, to increase the stability of the formulation, for aesthetic reasons or for identification. Although excipients have traditionally been thought of as being inert, experience has shown that they can interact with a drug to affect its absorption and bioavailability. Indeed, some excipients are added to a formulation specifically to take advantage of the interaction when it affects the bioavailability of the drug. This article gives an overview of the physicochemical and physiological processes [e.g. stability, physiological pH, gastrointestinal (GI) transit time, disintegration, dissolution and permeability] that can be altered by drugexcipient interactions. In addition, we give details of established mechanisms of interaction and, where possible, show the potential impact of these interactions on the absorption and bioavailability of the drug. Excipients have traditionally been classified according to the function they perform in a formulation, although many excipients perform multiple functions. Diluents allow the formulation of a practically sized tablet and can form a

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general circulation and hence transported to its site of action. Most drugexcipient interactions that have been identified affect the processes of disintegration and/or dissolution. Effects on physiological factors or processes such as the pH of the microenvironment, the stability of a drug substance in the GI tract and the permeability of GI membranes to the drug can also alter the bioavailability of a drug, however, a significantly smaller number of reports have been published on these types of interactions. Disintegration Disintegration is the process whereby the dosage form breaks up into fragments and particles, exposing a large surface area of drug product to the physiological fluids and thus allowing dissolution to occur more readily. There are official in vitro disintegration tests and these are described in national and international pharmacopoeias such as the US Pharmacopoeia13 (USP) and the British Pharmacopoeia14 (BP). If a drugexcipient interaction results in more rapid disintegration, then absorption will increase if disintegration is a critical step for that particular drug. For example, the antidiabetic drug tolbutamide was spray dried in combination with a disintegrant [partly pregelatinized corn starch (PCS)] to form particles composed of a single core of PCS on which the drug was deposited15. Increased dissolution was observed compared with a formulation made with regular corn starch; this was caused by the layer of drug crystals separating from the surface of the particle owing to rapid disintegration caused by the swelling action of PCS. A study on the hydrophobic diuretic drug furosemide investigated the effect of formulations with different disintegrants16.The superdisintegrant sodium starch glycolate was found to increase the bioavailability of furosemide significantly in comparison with other disintegrants. A drugexcipient interaction that results in inadequate or very slow disintegration of a drug product will reduce the bioavailability of the drug if disintegration is a rate-limiting step in its absorption. For example, when the bioavailability of six commercial formulations of the antihelmintic agent praziquantel were investigated, in vitro disintegration testing showed that one generic formulation failed to disintegrate in water and acidic media, and subsequently failed to dissolve adequately17. When this formulation was administered in vivo, its bioavailability was lower than those of the other formulations. When the antibacterial drug sulphadimidine was formulated with various disintegrants including Primojel (sodium starch glycolate), Veegum and Amberlite, a decrease in disintegration and dissolution times was observed3.The magnitude of the reduction in these times differed depending on the disintegrant used perhaps as a result of the differences in binding between the sulphadimidine and the different disintegrants. In a study of oxymorphone derivatives formulated with the

superdisintegrant croscarmelose sodium, there was extensive binding of the oxymorphone to the croscarmelose sodium, which resulted in a slower rate of dissolution18. Dissolution A drug has to be in solution before it can be absorbed across the GI membranes and reach the systemic circulation. Because many drugs are lipophilic, dissolution is often the rate-limiting step in absorption. Thus, drugexcipient interactions that alter dissolution can have a significant impact on absorption. In vitro experiments were conducted with formulations of the anti-inflammatory drug phenylbutazone in which possible drugexcipient interactions were identified for three of the ten formulations19.Two of these formulations had slow dissolution rates and low bioavailabilities, but the third formulation had a slow rate of dissolution yet its bioavailability was ~100%. In a study of four formulations of the antidiabetic drug tolazamide, one formulation exhibited fast dissolution and high bioavailability20.Two other formulations showed intermediate dissolution but, in vivo, one of them had a high bioavailability and the other a significantly lower availability. These inconsistent effects on dissolution suggest that dissolution might not be the rate-limiting step for these drug formulations. One study evaluated eight different formulations of the diuretic spironolactone in which concentrations of talc, magnesium stearate and gelatin were varied with each formulation21. A wide disparity was found between the disintegration times and the rates and extents of dissolution, yet no significant differences were observed in the bioavailability of these products. In another study evaluating spironolactone formulations, when calcium sulfate dihydrate was substituted with dibasic calcium phosphate as the major tablet excipient, dissolution was very slow yet there was no appreciable effect on bioavailability22. In contrast to the previous studies, Chao and co-workers found that the bioavailability of spironolactone was correlated with dissolution when the levels of microcrystalline cellulose, starch and calcium sulfate dihydrate were varied among different formulations23. An interaction was observed in a series of studies conducted to investigate different formulations of the antibiotic amoxycillin with various excipients (colloidal silica and a synthetic fat derivative of glycerin and talc)2426. When synthetic fat and talc were the only excipients in the formulation, there was an increase in dissolution and an increase in bioavailability as the proportion of fat decreased. However, when colloidal silica was added to the formulation, increased bioavailability of amoxycillin was observed at high concentrations of silica irrespective of the fat content. When the calcium-channel blocker nifedipine was co-ground with polyethylene glycol 6000 (PEG6000) and
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Figure 1. Increased area under the plasma-concentrationtime curve when nifedipine is administered as a co-ground mixture compared with a physical mixture. Mean plasma-concentrationtime profiles of nifedipine (NP) after the oral administration of various preparations equivalent to 10 mg of NP to beagle dogs. Each point represents the average of four determinations, plus or minus the standard error. Physical mixture (closed circle); co-ground mixture prepared in the presence of water (closed square); NP solution of PEG400 (open square). Reproduced, with permission, from Ref. 28.

hydroxypropylmethyl cellulose (HPMC) in the presence of a small amount of water, the rate of dissolution of the co-ground mixture was markedly higher than that of a physical mixture27. The authors suggested that hydrophobic interactions between nifedipine and the polymer occurred during the co-grinding process.When the co-ground mixture was administered to dogs, there was a tenfold increase in the maximum concentration (Cmax) and a threefold increase in the area under the concentrationtime curve (AUC) of the co-ground mixture compared with the physical mixture (Fig. 1). In this case, the method of manufacture of the drug product resulted in an increased interaction between the drug and the excipient, causing an increase in dissolution and a subsequent increase in absorption. Physiological factors and processes Drugexcipient interactions have the potential to affect many physiological processes and factors, such as the pH of the microenvironment, protein binding, GI transit time, stability in the GI tract, effects on gut flora, and so on. The potential outcome of all of these interactions might be to alter the bioavailability of the drug. Although examples of drugexcipient interactions affecting all of these processes and factors were not found during a literature search, it does not mean that examples have not occurred and these potential areas for interaction should be considered if unexpected effects occur upon the administration of a formulation in vivo.
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If significant degradation or decomposition of a drug occurs, this can result in less absorption and a lower bioavailability of the drug. Chlorpromazine is an antipsychotic drug known to undergo metabolic transformation in the gut28. The stability of chlorpromazine was improved when it was administered as a complex with -cyclodextrin and this resulted in an increase in bioavailability. In a study evaluating formulations of the non-steroidal anti-inflammatory drug (NSAID) aspirin, the effect of gluconolactone as a direct compression diluent was compared with the established diluent, anhydrous lactose29. There was less hydrolysis of aspirin when it was formulated with gluconolactone. In contrast to the effect seen in the chlorpromazine study, preliminary in vivo studies with the aspiringluconolactone formulation showed no significant effect on the bioavailability of aspirin. The pH of the GI tract varies greatly, from pH 13.5 in the stomach to pH 78 in the large intestine5,30. Some drugs can be preferentially absorbed from a particular section of the gut, although both weakly acidic and basic drugs are absorbed from the small intestine. Drugs that are weak acids are un-ionized in the stomach and hence might be absorbed well from there, whereas drugs that are weak bases might not be well absorbed from the stomach because they are highly ionized. A substance that increases the gastric pH would therefore be expected to increase the absorption of weak bases and to decrease the absorption of weak acids in the stomach30,31. The antibiotic erythromycin acistrate is an erythromycin derivative that is susceptible to conversion to anhydroerythromycin in the acidic contents of the stomach32. Formulating erythromycin acistrate as a hard gelatin capsule with sodium bicarbonate as an excipient resulted in an increase in the pH of the stomach, which led to increased bioavailability of erythromycin32. A study evaluating the bioavailability of the poorly water soluble drug tolbutamide from four commercial preparations found that the dissolution of one preparation at pH 6.5 took 900 min (Ref. 33). However, no significant difference in urinary recovery was found compared with the other formulations.The authors changed the dissolution testing conditions to incorporate pre-incubation of the formulation in acidic media, a situation that reflects physiological conditions more accurately, and this resulted in rapid disintegration and a more rapid dissolution of the preparation. For some drugs, one of the tasks of the pharmaceutical scientist is to formulate the drug in such a manner that it will be preferentially released in a certain part of the GI tract. The H2-receptor antagonist ranitidine, which is preferentially absorbed proximal to the cecum, was formulated with sodium acid pyrophosphate as an excipient to make an effervescent tablet34. When it was tested in vivo, the extent of absorption was found to be approximately half of that seen with the regular

Plasma concentration of NP (ng ml1)

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Table 1. Summary of studies involving cyclodextrins

Drug Spironolactone Atovaquone Oxazepam Griseofulvin Ursodeoxycholic acid Cinnarizine Naproxen Tolbutamide Cyclodextrin SBE--CD, DM--CD SBE--CD, HP--CD -CD -CD HP--CD SBE--CD, HP--CD -CD -CD Effect on dissolution Increased Increased Increased Increased Increased Increased Increased Increased In vivo study Rats Dogs ND Rabbits and humans Humans Dogs Humans Rabbits Effect on bioavailability Increased Increased NA Increased Increased Increased No effect No effect Ref. 43 47 89 44 45 46 48 49

Abbreviations: -CD, -cyclodextrin; HP--CD, hydroxypropyl--cyclodextrin; SBE--CD, sulfobutylether--cyclodextrin; DM--CD, dimethyl--cyclodextrin; ND, not done; NA, not applicable.

tablet formulation. Investigations revealed that the small intestinal transit time of the effervescent formulation was much more rapid than that seen with the tablet formulation. Similarly, a study investigating another H2-receptor antagonist, cimetidine, formulated with either mannitol or sucrose found that mannitol formulations reduced the small intestinal transit time of cimetidine compared with sucrose, which led to a reduced oral bioavailability35. It has been suggested that both sodium acid pyrophosphate and mannitol act as small intestinal cathartics even at these low concentrations, which results in a decrease in small intestinal transit time36. However, the effect of mannitol had been shown to be concentration dependent and therefore using a lower concentration of mannitol in a formulation might not affect bioavailability37. Mechanisms of drugexcipient interactions A review of the literature on drugexcipient interactions shows that the mechanism of the interaction is often not clear. However, there are several well-documented mechanisms in the literature, and these are described here with examples to illustrate the effect. Complexation Complexing agents interact, usually reversibly, with a drug to form a complex5,31. When in the complex, the drug is not free to dissolve because it must first dissociate from the complex31. In many instances, the drug complex will dissociate upon coming into contact with GI fluids, releasing the drug substance, which can then be absorbed across the GI membranes. Complexing agents such as cyclodextrins are often used to increase the bioavailability of poorly water soluble or unstable drugs. Cyclodextrins are cyclic oligosaccharides that are composed of a small number of dextrose units. The inside of these molecules is lipophilic and the exterior is relatively hydrophilic. It is this lipophilic interior of cyclodextrin molecules that allows the formation of inclusion complexes with hydrophobic

drugs38,39. Cyclodextrins can be used to increase absorption and bioavailability by increasing the rate and extent of drug dissolution, by increasing the permeability of the mucosal membrane or by increasing the stability of the drug38,40. There are numerous articles in the literature reviewing the use of cyclodextrins in the pharmaceutical formulation of oral products38,4043. A summary of some studies that have evaluated the use of cyclodextrins as complexing agents in oral formulations is shown in Table 1. Studies conducted with numerous different drugs such as griseofulvin44, ursodeoxycholic acid45, cinnarizine46, and atovaquone47 in combination with various cyclodextrins all demonstrate marked improvement in bioavailability caused by increased dissolution. Figure 2 shows the twofold increase in Cmax and AUC observed after administering a bile acid (ursodeoxycholic acid) complex compared with a commercial preparation. However, complexation with cyclodextrins has not been shown to increase the bioavailability of all poorly soluble drugs. Even though the extents of dissolution of the NSAID naproxen48 and tolbutamide49 were increased by complexation with cyclodextrins, there was no corresponding increase in bioavailability48,49. Complexation of a drug can also result in decreased bioavailability. For example, the antibiotic tetracycline forms an insoluble complex with calcium carbonate, which results in slower dissolution and less absorption50. Similarly, the anti-epileptic drug phenobarbital was shown to form an insoluble complex with PEG4000 (Ref. 51). Formation of the complex resulted in decreased dissolution and decreased absorption to approximately one-third of that for phenobarbital alone. In a study evaluating commercial formulations of the steroid prednisolone, five preparations showed increased in vitro dissolution compared with the powder alone52. This was attributed to the formation of complexes with water-soluble excipients in the formulations. However, in vitro experiments showed that these complexes had high molecular weights and might be too large
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Figure 2. Increased area under the plasma-concentrationtime curve of ursodeoxycholic acid (UDCA) when complexed with a cyclodextrin compared with a commercial preparation of UDCA. Mean UDCA plasma concentrations (n 6) after oral administration of tablets containing 425 mg UDCA in an inclusion complex with 2-hydroxypropyl--cyclodextrin (closed square) or of commercial tablets containing 450 mg free UDCA (closed triangle). Bars represent the standard deviation. Reproduced, with permission, from Ref. 46.

to diffuse through GI membranes. Thus, although dissolution increased, it is possible that the in vivo bioavailability would be lower. Other in vitro studies investigated the effect on membrane permeability of adding polysorbate 80 and sodium lauryl sulfate to chlorpromazine formulations53. In both cases, a decrease in permeability was observed. Polysorbate 80 has a very low critical micelle concentration and so the decrease in permeability was attributed to formation of soluble micellar aggregates. However, in the case of sodium lauryl sulfate, which has a higher critical micelle concentration, it appeared that an insoluble complex was formed between the lauryl sulfate anions and the chlorpromazine cations. Adsorption The adsorption of drug molecules onto the surface of excipients can reduce drug particle size and increase the surface area of drug available to the dissolution medium16,54,55. Both of these effects might increase dissolution and, as a result, bioavailability. In a study of the weak acid dicumarol, magnesium hydroxide and magnesium oxide enhanced its absorption in dogs as a result of increased dissolution56. This was attributed to the formation of a more readily absorbable dicumarolmagnesium chelate or to an increase in pH of the microenvironment
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caused by the addition of the excipients. When indomethacin, an NSAID, was formulated as an absorbate with kaolin, an increase in dissolution was observed compared with a simple mixture of the two components54. The authors suggested that, when the adsorbate was formed, drug crystallized on the surface of the adsorbent particles, increasing the surface area of drug available for dissolution. Adsorption of drug molecules can render the drug unavailable for dissolution and diffusion and this might, in turn, reduce bioavailability5. When the lubricant magnesium stearate was added to tablets containing cetylpyridinium chloride, there was a marked reduction in antibacterial activity owing to adsorption of the cetylpyridinium chloride cations by stearate anions on the surface of the magnesium stearate particles57. Similarly, the use of colloidal magnesium aluminum silicate, aluminum hydroxide, starch and talc in formulations with dicumarol resulted in decreased absorption of dicumarol attributed to the adsorptive properties of the excipients56. A similar potential effect of talc was identified for the anxiolytic agent chlordiazepoxide using membrane permeability studies, although the quantities of talc used were larger than would be expected in practice58. Potential bioavailability problems were identified for chlorpromazine through in vitro studies that showed chlorpromazine adsorbed to the surface of talc and kaolin resulting in reduced membrane permeability53. Similarly, the benzodiazepine diazepam, which exists predominantly in the cationic form at low pH, was found to adsorb to the negative sites on kaolin and talc59. The authors did not investigate the effect of this binding on the dissolution and bioavailability of diazepam. A substantial electrostatic interaction has been observed in vitro involving croscarmelose sodium, which is negatively charged at pH2, and the cation of a weakly basic antihistamine, chlorpheniramine maleate60. However, when croscarmelose sodium was added to a formulation of another weakly basic drug, phenylpropanolamine, which is used in cold preparations, no effect was observed in vivo, indicating that this type of interaction might not occur at the low pH of physiological fluids61. Adsorption can be reversible and might not affect the bioavailability of the drug. When several other drugs, such as griseofulvin, indomethacin and prednisone, were formulated as adsorbates with colloidal magnesium aluminum silicate, a marked increase in dissolution of all drugs was observed62. It was thought that the drugs bound to the surface of the colloidal magnesium aluminum silicate by weak van der Waals forces. The hydrophilic and swelling properties of the colloidal magnesium aluminum silicate facilitated wetting of the drug and therefore the bonds were easily broken to release the drug again.

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Table 2. Summary of studies investigating the use of solid dispersions

Drug Excipient(s) Binary or Effect on In vivo ternary system dissolution study B B B B and T B and T B and T B T T B and T B T B Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Rabbits Rabbits Rabbits Rats ND ND ND Humans Dogs ND ND ND Effect on bioavailability Increased Increased Increased Increased NA NA NA Increased Increased NA NA NA Method of preparation Fusion Melting Ref.

Piroxicam Norfloxacin Norfloxacin Nifedipine Oxodipine Griseofulvin Ibuprofen Rev5901 Rev5901 Mefenamic acid Ciprofloxacin Rev5901 Indomethacin

PEG4000/6000 PEG6000 PEG6000 PEG4000 and PEG4000/PC PEG6000 and PEG6000/Tween 20 PEG6000 and PEG6000/Tween 20 PEG4000 or PVP PEG400 and GP PEG1000 and GP PEG3350 and PEG3350/Tween 20 PEG6000 PEG (various grades) and polysorbate 80 HPC-SL and HPMC

64 65 66 Solvent 67 Melting 68 Melting 68 Melting and 69 solvent Not stated 73 Not stated 74 Melting 70 Melting 63 Melting 75 71

Humans Increased rate of absorption; Solvent no effect on extent of absorption

Abbreviations: PEG, polyethylene glycol; PC, phosphatidylcholine; PVP, polyvinyl pyrrolidine; GP, mixture of glyceryl and PEG1500 esters of long chain fatty acids; DMPC, dimyristoylphosphatidylcholine; HPC-SL, hydroxypropyl cellulose-SL; HPMC, hydroxypropylmethyl cellulose; B, binary system (drug plus one component); T, ternary system (drug plus two components); ND, not done; NA, not applicable.

Solid dispersions The formulation of hydrophobic drugs as solid dispersions is a significant area of research aimed at improving the dissolution and bioavailability of hydrophobic drugs. Solid dispersions consisting of two components in the solid state are referred to as binary systems. The two components are a water-soluble carrier and a hydrophobic drug dispersed in the carrier substance63. Several different methods have been used to formulate solid dispersions and the particular manufacturing method used might influence the in vivo effect of the drug. A summary of selected studies using solid dispersion methodology is provided in Table 2. Different molecular weights of PEG have been used to formulate solid dispersions with many different types of drugs, including piroxicam64, norfloxacin65,66, nifedipine67, oxodipine68, griseofulvin68 and ibuprofen69. In all cases, an increase in dissolution of the drug from the solid dispersion was observed compared with either the drug alone or a physical mixture of the drug with PEG. This latter effect shows that the interaction of the drug with PEG to form the solid dispersion is at least partly responsible for the increased dissolution. In the studies that evaluated the solid dispersions in vivo, a corresponding increase in bioavailability was observed. It has been proposed that PEG acts as a disaggregant in a physical mixture, reducing the electrostatic charges between the drug particles, thereby facilitating dissolution68. When the

solid dispersion is formulated, crystals of the drug in combination with the PEG are formed.There might be a corresponding decrease in particle size and a resulting increase in surface area, or there might be a decrease in the force of interaction between the drug molecules, both of which would cause a further increase in dissolution64,68. Although PEG has been the most frequently used hydrophilic carrier, other water-soluble carriers have also been used, such as polyvinyl pyrrolidine (PVP) and HPMC27,70,71. The commercial use of solid dispersions has been limited by difficulties with manufacturing and stability. However, the overall effect of formulating a poorly water-soluble drug as a solid dispersion in a water-soluble carrier appears to be to increase dissolution and, where tested, to increase bioavailability. This indicates that this technique does have value in pharmaceutical manufacturing if the problems can be overcome. However, there are examples in which it has not resulted in improved absorption.When indomethacin was formulated with hydroxypropyl cellulose-SL, a 30-fold increase in dissolution was observed for the solid dispersions compared with the drug alone71. This resulted in a faster rate of absorption for the solid dispersions but the overall extent of absorption was comparable to that observed for the pure drug. Only binary solid dispersions have been discussed so far but ternary systems can also be formulated.These include a second excipient, such as a surfactant, to increase dissolution further.
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The addition of surfactants can often markedly increase the dissolution rates of hydrophobic drugs by increasing contact between the drug and the dissolution medium72. Surface active agents that have been included in solid dispersions for this purpose include Tween 20, phosphatidylcholine, polysorbate 80 and sodium lauryl sulfate6770,7375. All studies found increased dissolution and those studies that included in vivo data also reported increased bioavailability. The surfactant probably decreases the interfacial tension between the dissolution medium and the drug particles, thereby facilitating wetting of the drug and increasing dissolution. One study postulated that the surfactant acted to prevent a drug-rich layer forming on the surface of the solid dispersion, which was impeding dissolution of the formulation75. Chemical interaction Several different types of chemical drugexcipient interactions have been reported in the literature. To illustrate the potential consequences of an unexpected drugexcipient interaction, consider the occurrences of phenytoin toxicity that were observed in the late 1960s in Australia in epileptic patients taking phenytoin sodium preparations7678. Patients presented with a variety of symptoms associated with phenytoin toxicity including double vision, vomiting, ataxia, psychiatric disturbances and high plasma phenytoin levels. It was found that toxicity occurred when patients who were stabilized on phenytoin were changed from a formulation containing calcium sulfate as the major excipient to a formulation containing lactose instead. Use of the formulation with lactose resulted in much higher blood phenytoin levels than observed with the calcium sulfate formulation. It was thought that calcium sulfate might interact to form an insoluble form of phenytoin that could not be absorbed across the cell membranes of the gut wall, although this was not shown conclusively to be the case76,79,80. An alternative explanation for this effect was incomplete release of phenytoin sodium from the capsules in the presence of calcium sulfate dihydrate. However, a previous in vivo study had shown that almost all of the administered dose could be accounted for76,80.This shows that careful consideration must be given to reformulating an established drug, especially a drug with a narrow therapeutic index, such as phenytoin. When silica gel was added to vitamin formulations containing ascorbic acid, the decomposition of ascorbic acid increased, possibly as a consequence of the trace metals such as iron and copper present in silica gel, which can catalyse the decomposition of ascorbic acid in solution81. However, bioavailability was not affected. Other investigators found that the polymer chitosan inhibited the release of the NSAID diclofenac sodium from matrix tablets at low pH, possibly
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through the formation of an ionic complex between the diclofenac sodium and the ionized amino groups of the cationic polymer82. An in vitro study found that chlordiazepoxide, which can exist in cationic form, formed an ion pair with the anionic surfactant sodium lauryl sulfate, resulting in decreased membrane permeability4. Finally, when ibuprofen and ketoprofen were formulated with the organic base N-methylglucamine, an increase in dissolution was observed with both of these NSAIDs83. Ibuprofen appeared to form a complex with the N-methylglucamine, but the authors also proposed the formation of water-soluble salts as a potential explanation for this effect83. Regulatory implications Although the previous sections of this article describe how drug and excipients might interact to alter absorption, the lack of an in vivo effect has become even more important to the regulatory agencies and the pharmaceutical industry. In recent years, in the USA, there has been a significant amount of interest and effort in defining formulation changes that will not significantly alter absorption. This interest has led the FDA, the pharmaceutical industry and academia to investigate scientifically and to discuss how formulations can be changed without altering the in vivo response. This led to the FDA guidelines on scale-up and post-approval changes (SUPAC). In 1995, the FDA issued a guidance document governing changes to immediate release formulations84, SUPAC-IR and, in 1997, a similar document was issued governing changes to modified release formulations85, SUPAC-MR. The purpose of the guidelines was: (1) to decrease the amount of information and in vivo studies required when insignificant (from an in vivo point of view) changes in the formulation were made; (2) to define different levels of change and the information required for various changes; (3) to pre-define some significant and insignificant formulation changes to the pharmaceutical industry; (4) to ensure that critical and non-critical formulation variables would be investigated using the appropriate scientific approaches; and (5) to ensure that formulation changes would be made without compromising the safety and efficacy of the formulation. The science for these guidelines was based on the experiments conducted at the University of Maryland (MD, USA) in conjunction with the FDA, as well as the collected knowledge of scientists within the FDA, pharmaceutical industry and academia. The University of MarylandFDA collaboration investigated various compositional and manufacturing changes made to a series of formulations and quantified the effects that these changes had on the in vitro and in vivo activity of the drug; various different drugs were used in these studies (e.g. piroxicam, propranolol, metoprolol, naproxen, naproxen sodium, ranitidine

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and diltiazem). The results of the experiments conducted with the NSAID piroxicam and the beta blockers propranolol and metoprolol have been published8688, and the results of the other drugs have been presented in other forums. An example of these findings is the investigation of 19 piroxicam formulations in which excipients and manufacturing processes were varied86. Three formulations representing slow, medium and fast dissolution were then administered in vivo in addition to the innovator product. In vitro dissolution profiles were found to be markedly different for the various formulations but no apparent differences were observed in vivo. The results of these experiments showed that these drugexcipient interactions only affected the in vitro dissolution of the drug. The changes in excipients evaluated in these studies did not appear to be critical variables in the manufacture of this particular drug. Conclusions Traditionally, excipients have been regarded as inert. However, there are many instances in which excipients have been shown to have a significant effect on the biological availability of the drug. Many of the drugexcipient interactions affected the process of dissolution. In fact, an interaction between a drug and an excipient that alters the dissolution of some hydrophobic drugs has been shown to have a marked impact on the absorption and bioavailability of that drug. This is certainly the case where dissolution is the rate-limiting step in absorption. A drugexcipient interaction can be actively used to the advantage of the formulator to increase the bioavailability of the drug (e.g. complexation with cyclodextrins or solid dispersion technology). However, there are also many cases in which an interaction might not be expected and might adversely affect the bioavailability of a drug (e.g. where the mechanism of the interaction is surface adsorption or increased GI transit time). This article has referenced only published literature describing drugexcipient interactions and the effect or lack of effect on absorption. As we know of other confidential drugexcipient interaction studies that have not been reported in the literature, it is highly likely that the information reported herein is just a small portion of the scientific investigations that have been performed in this area. A more complete review of this scientific area will, however, only be possible when the proprietary information is made available by the pharmaceutical industry, and this might never happen. References
1 2 Gennaro, A.R., ed. (1990) Remingtons Pharmaceutical Sciences (18th edn), pp. 16331639, Mack Publishing Company, Easton, PA, USA Yen, J.K.C. (1964) The dissolution rate principle in practical tablet formulation. Can. Pharm. J. 26, 493499

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Aboutaleb, A.E. et al. (1983) Effect of various disintegrants on the availability of directly compressed sulphadimidine tablets. Pharmazie 38, 473475 Lieberman, H.A. et al., eds (1989) Pharmaceutical Dosage Forms (2nd edn), Marcel Dekker Banker, G.S. and Rhodes, C.T., eds (1996) Modern Pharmaceutics (3rd edn), Marcel Dekker Wade, A. and Weller, P.J. (1994) Handbook of Pharmaceutical Excipients (2nd edn), American Pharmaceutical Association and the Royal Pharmaceutical Society of Great Britain

Bolhuis, G.K. et al. (1997) Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant, II.The choice of super disintegrants and effect of granulation. Eur. J. Pharm. Sci. 5, 6369

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Itiola, O.A. and Pilpel, N. (1986) Studies on metronidazole tablet formulation. J. Pharm. Pharmacol. 38, 8186 Lin, S-Y. (1988) Effect of excipients on tablet properties and dissolution behavior of theophylline-tableted microcapsules under different compression forces. J. Pharm. Sci. 77, 229232

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