Pharmaceutical
`Preformulation and
`Formulation
`
`
`
`
`
`
`A Practical Guidefirom Candidate Drug
`Select toComme aphase Form
`~~Ga
`
`MYLAN EXHIBIT 1022
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`1408_FM 6/10/03 10:46 AM Page i
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`PHARMACEUTICAL
`PREFORMULATION
`AND
`FORMULATION
`
`A Practical Guide from
`Candidate Drug Selection to
`Commercial Dosage Form
`
`Mark Gibson
`Editor
`
`IHSfi Health Group
`
`An IHSfi GROUP Company
`
`Your Enterprise Solution to (cid:31)
`Global Healthcare Knowledge
`
`

`

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`disclaimer Page 1 Monday, June 9, 2003 12:22 PM
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`1408_Chapter 04II 6/10/03 10:34 AM Page 97
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`4
`
`Biopharmaceutical Support in
`Candidate Drug Selection
`
`Anna-Lena Ungell
`Bertil Abrahamsson
`AstraZeneca
`Mölndal, Sweden
`
`Adminstration via the oral route has been, and still is, the most popular and convenient route
`for patient therapeutics. However, even though it is the most convenient route, it is not the
`simplest route, as the barriers of the gastro-intestinal (GI) tract are in many cases difficult to
`circumvent. The main barriers of the GI tract to systemic delivery are the environment in the
`stomach and intestinal lumen, the presence of different enzymes, the physical barrier of the
`epithelium and the liver extraction. These barriers are of functional importance for the or-
`ganism in controlling intake of water, electrolytes and food constituents and still remain a
`complete barrier to harmful organisms such as bacteria, viruses and toxic compounds.
`Generally, drug absorption from the GI tract requires that the drug is brought into solu-
`tion in the GI fluids and that it is capable of crossing the intestinal membrane into the sys-
`temic circulation. It has therefore been suggested that the drug must be in its molecular form
`before it can be absorbed. Therefore, the rate of dissolution of the drug in the GI lumen can
`be a rate-limiting step in the absorption of drugs given orally. Particles of drugs, e.g., insolu-
`ble crystalline forms or specific delivery systems such as liposomes, are generally found to be
`absorbed to a very small extent. The cascade of events from release of the drug from its dosage
`form, i.e. dissolution of the drug in the gut lumen, interactions and/or degradation within the
`lumen and the uptake of its molecular form across the intestinal membrane into the systemic
`circulation, is schematically shown in Figure 4.1. For rapid and effective design and develop-
`ment of new drug products, methods for drug absorption are required that describe the dif-
`ferent steps involved before and during the absorption process. The need for such specific
`
`97
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`Pharmaceutical Preformulation and Formulation
`
`Figure 4.1 Drawing showing the different steps in the absorption process including the
`dissolution of the compound from the solid dosage form, interactions with the dissolved
`material in the gastro-intestinal lumen and the uptake of the compound through the
`epithelial membrane.
`
`Solid dosage form Drug in solution Absorbed drug
`Uptake/absorption
`Dissolution
`
`Interactions
`Enzymatic degradation
`
`methods is determined by the information on the rate-limiting step in the cascade of events
`(e.g., solubility, permeability or metabolic instability limited). The results from these methods
`act as a guide to a more efficient discovery process in which resources are given to optimising
`structures that lead to the selection of a good drug candidate with well-defined pharmacoki-
`netic and physicochemical properties. A method now available is multivariate analysis for
`analysing large data sets. Screening and optimisation of several parameters in parallel, e.g.,
`permeability, metabolic stability, solubility, potency, duration and toxicity, represent a grow-
`ing area for rationalising drug discovery using multivariate statistical models (Eriksson et al.
`1999). The importance of this is obvious: There is no point in using resources to increase the
`potency of an oral drug candidate if the drug is not predicted to be orally bioavailable. The
`consideration of biopharmaceutical properties in the selection of candidate drugs has also
`been shown in a recent survey, based on statistics published by the Pharmaceutical and Re-
`search Manufacturers of America (PhRMA), to be the most common reason for terminating
`drug development projects in the clinical phase.
`The dissolution rate and/or the aqueous solubility of the drug will also affect the outcome
`of studies using biological methods, in very early phases of screening. If not dissolved in the
`test system, low solubility drugs will not appear on the receiver side/blood side of a membrane
`or will show incomplete absorption in vivo. Consequently, the drug will be considered a low
`permeability drug and be discarded as being of no potential use as a systemically active drug.
`The situation is even more complex, since there are also mechanistic membrane processes that
`can give the same result. Such processes include drug efflux systems that transport the drug
`from inside the epithelial cell to the lumen of the intestine [e.g., efflux proteins (Hunter and
`Hirst 1997)] or metabolism during transport and adhesion to plastics in the test system (Table
`4.1). The evaluation of the reason for low transport is therefore crucial for the design of
`proper screening procedures.
`In the drug discovery process, the selection of a suitable candidate drug is the milestone
`for continuing into a costly development and clinical phase. Some optimal absorption criteria
`from a biopharmaceutical point of view are shown below:
`
`• High permeability coefficient (determined using in vitro assays such as Caco-2 cell
`monolayers, Ussing chambers, intestinal perfusions, etc.; see below) throughout the
`GI tract [Extended Release (ER) formulation]
`
`

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`Biopharmaceutical Support in Candidate Drug Selection
`
`99
`
`Table 4.1
`Suggested reasons for low permeability values
`during transport studies with in vitro models.
`
`Adhesions to plastics
`Low solubility
`Complexation with ions in the buffer
`Metabolism in the lumen or in the intestinal segment
`Low activity/viability of the tissue (active transport)
`Analytical problems (analytical response limited)
`Large UWL (unstirred water layer) or mucus layer (unstirred models)
`True low permeability
`
`•
`
`Passive diffusion–directed transport or known mechanism for carrier-mediated
`transport or interaction
`
`• High solubility in aqueous media and over a wide pH range (e.g., pH 1–7).
`
`•
`
`•
`
`No degradation/metabolism in intestinal luminal fluids, intestinal homogenates
`and/or microsomal preparations from the intestine and liver (i.e., low first-pass
`metabolism)
`
`Complete absorption in the GI tract in vivo in several animal species
`
`These criteria are usually difficult to achieve, and the relationship between the in vitro effect of
`the drug (potency/concentration needed), therapeutic effect and index (acceptable variation in
`plasma concentration from safety and efficacy point of view) and the rate and extent of ab-
`sorption must therefore be evaluated carefully for each project and drug. Furthermore, the
`physicochemical characteristics (e.g., the ability of the drug to be formulated into a relevant
`delivery system) of the drug as determined in preformulation studies also guide the selection
`of a potential drug candidate.
`The biopharmaceutical information gathered in the candidate drug selection process re-
`garding the characteristics of the drug molecule (e.g., dissolution, solubility, stability in fluids
`at the site of administration, enzymatic stability, membrane transport and bioavailability) is
`also very useful as input to the subsequent formulation development. This information is im-
`portant, for example,
`
`•
`
`•
`
`•
`
`•
`
`to determine suitable formulation types and technologies,
`
`to set biopharmaceutical targets for formulation development,
`
`to define initial biopharmaceutical test methods and studies needed to reach the
`targets and
`
`as background data for interpretation of different studies used in the development of
`a formulation.
`
`

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`Pharmaceutical Preformulation and Formulation
`
`Thus, a well-performed drug substance characterisation minimises the risk of a subopti-
`mal final formulation as a result of neglecting important biopharmaceutical prerequisites for
`a certain drug substance. Furthermore, such information also allows an efficient development
`process based on science, while trial and error approaches are avoided.
`The ideal model for the biopharmaceutical assessment of drug transport, metabolism and
`dissolution should have certain characteristics, i.e., should represent the main physiological or
`physicochemical barrier as relevantly as possible to the human in vivo situation. No single
`method can represent all barriers and at the same time give information about the mecha-
`nisms underlying the absorption process. Furthermore, no single method can provide all the
`information needed, from the synthesis of a series of compounds in the screening phase (dis-
`covery) to the development of the specific formulation intended for human use. Many differ-
`ent methods have been developed over the last 20 years for use in different phases of drug
`discovery and development. This chapter will deal with some of these techniques to gain a
`basic knowledge of drug absorption. Also, it will give a description of related methods, and the
`functional use of the information provided by these methods, to aid in the selection of a can-
`didate drug and the development of formulations intended for use in humans.
`
`DRUG DISSOLUTION AND SOLUBILITY
`
`Drug dissolution is a prerequisite for oral absorption. Thus, a drug that is not fully dissolved
`cannot be completely absorbed through the GI epithelium. It is thus extremely important to
`understand drug dissolution and solubility in aqueous media, both in early drug discovery
`studies and as a prerequisite for the subsequent formulation development. More specifically,
`drug dissolution/solubility data give important information that provides answers to the fol-
`lowing biopharmaceutical questions during the discovery phase:
`
`• Will the drug absorption be limited by the drug dissolution/solubility?
`
`• Will the drug dissolution/solubility limit the bioavailability to an extent that endan-
`gers the clinical usefulness of the drug?
`
`• Which types of vehicles are needed in preclinical studies to provide the desired drug
`exposure?
`
`•
`
`Should the substance form be changed to improve dissolution (e.g., salt, polymorph,
`particle size)?
`
`After the choice of a candidate drug, solubility and dissolution data are used for guidance
`in the following:
`
`•
`
`•
`
`Should dissolution rate-enhancing principles be applied in the formulation develop-
`ment (e.g., wetting agents, micronisation, solubilising agents, solid solutions, emul-
`sions and nanoparticles)?
`
`In the case of modified release formulations, which formulation principles are suit-
`able and which release mechanisms can be expected?
`
`• Which test conditions should be used for in vitro dissolution testing of solid formu-
`lations?
`
`

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`Biopharmaceutical Support in Candidate Drug Selection
`
`101
`
`It should be emphasised that dissolution is the dynamic process by which a material is dis-
`solved in a solvent and is characterised by a rate (amount dissolved per time unit), while sol-
`ubility is the amount of material dissolved per volume unit of a certain solvent. Solubility is
`often used as a short form for “saturation solubility”, which is the maximum amount of drug
`that can be dissolved at equilibrium conditions. Finally, the term intrinsic solubility is some-
`times used as well, which is the solubility of the neutral form of a proteolytic drug.
`Theoretically, the dissolution rate is most often described by the Noyes-Whitney equation
`(equation 1):
`
`D A
`dm
`¥
`)
`(
`Cs Ct
`-
`dt
`h
`where D is the diffusion coefficient of the drug substance in a stagnant water layer around
`each drug particle with a thickness h, A is the drug particle surface area, Cs is the saturation
`solubility and Ct is the drug concentration in the bulk solution. If the drug concentration in
`the bulk (Ct) in equation 1 is negligible as compared to the saturation solubility (Cs), the dis-
`solution rate is not affected by Ct. This state is denoted a “sink condition” and is often assumed
`to be the case in vivo, owing to the continuous removal of a drug from the intestine due to the
`absorption over the intestinal wall. A, Ct and h in equation 1 will be time dependent, whereas
`the other variables are constants at a certain test condition. The surface area (A) of a dissolv-
`ing particle will be constantly reduced by time (provided that no precipitation occurs); the
`thickness of the diffusion layer (h) is dependent on the radius of the particle size; and the bulk
`solution will increase toward its maximum when the total amount has been dissolved. In ad-
`dition, no solid drug powder is monodisperse, i.e., the starting material will consist of a dis-
`persion of different particle sizes with different surface areas (A). Extensions of equation 1
`have therefore been derived that take into account some or all of these factors. A full review of
`such equations and underlying assumptions, and a presentation of some other less used the-
`ories for dissolution, can be found elsewhere (Abdou 1989). A modification of equation 1 was
`recently presented that takes into account all time-dependent factors that can be useful for
`predictions of the dissolution rate (Hintz and Johnson 1989).
`Basic theoretic considerations and experimental methods regarding solubility are re-
`viewed in more detail in Chapter 3.
`The present chapter focuses on aspects of drug solubility/dissolution of specific relevance
`for biopharmaceutical support in candidate drug selection and preformulation. These aspects
`include solubility in candidate drug screening, physiological aspects of test media, solubility
`of amphiphilic drugs and substance characterisation prior to solubility/dissolution tests.
`
`˚ ¸`
`
`=
`
`(1)
`
`¥
`
`(cid:136) fl(cid:152)
`
`Aspects of Solubility in Candidate Drug Screening
`
`Although drug solubility is an important factor in drug absorption in the GI tract, it has not
`been extensively screened for as a barrier to absorption. Drug solubility should, however, be
`complementary to models predicting drug permeability through the lipid membrane. Solu-
`bility as a high-throughput screening (HTS) parameter has therefore been discussed rather in-
`tensively. The importance of solubility as a selective tool during early screening of hundreds
`of compounds, to choose a drug with a potential to be absorbed in vivo in humans, has not
`been fully evaluated, however. Several drugs that are very useful in the clinical situation have
`very low water solubility. For example, candesartan cilexetil, an effective and well-tolerated
`antihypertensive drug, has a water solubility of about 0.1 ␮g/mL. On the other hand, more
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 102
`
`102
`
`Pharmaceutical Preformulation and Formulation
`
`soluble drugs will minimise the risk of failure during the subsequent development phase and
`may avoid delays, increased costs or discontinuation of the project.
`Another aspect of solubility is seen during screening for good pharmacokinetic proper-
`ties of candidate drugs. The HTS systems or in vitro assays are the critical point for most drugs
`insoluble in water. This means that if the drug is not soluble in the buffer solution used in the
`in vitro system, it cannot be properly experimentally evaluated. The most common negative
`effect of this is that the concentration needed to induce transport across the epithelial mem-
`brane in the in vitro model is too low to be detected on the receiver side (see Table 4.1). For
`this reason, vehicles known to increase the solubility of sparingly soluble compounds are used
`(see section “Vehicles for Absorption Studies”). However, since these vehicles are based on sur-
`factant systems, toxic effects may be seen on the membrane (Oberle et al. 1995), and the per-
`meability values obtained may be overestimated. New methods are now available for screening
`large numbers of compounds in small volumes (e.g., the Nephelometer [BMG labtechnolo-
`gies GmbH]). This method is based on turbidimetric determinations and is therefore not an
`exact tool. It can, however, contribute substantially as a first estimate of solubility of sparingly
`soluble compounds and make it possible to understand the results of the screening methods
`and to design specific experiments using vehicles.
`
`Determinations of Drug Dissolution Rate
`
`The dissolution rate, rather than the saturation solubility, is most often the primary determi-
`nant in the absorption process of a sparingly soluble drug. Experimental determinations of
`the dissolution rate are therefore of great importance. The main area for dissolution rate stud-
`ies is evaluation of different solid forms of a drug (e.g., salts, solvates, polymorphs, amor-
`phous, stereoisomers) or effects of particle size. The dissolution rate can either be determined
`for a constant surface area of the drug in a rotating disc apparatus or as a dispersed powder in
`a beaker with agitation.
`The rotating disc method is in most cases the technique of choice for determining the drug
`dissolution rate of drug substances. Compressed discs of the pure drug without any excipients
`are placed in a holder (see Figure 4.2a, b). The disc is immersed in a dissolution medium and
`rotated at a high speed (e.g., 300–1000 rpm). The disc may be centrally or excentrally
`mounted to the stirring rod. The dissolution process is preferably monitored by on-line meas-
`urements of the dissolved drug. A more detailed description of the application of the rotating
`disc method in a preformulation programme can be found elsewhere (Niklasson et al. 1985).
`The dissolution rate is determined by linear regression from the slope of the initial linear
`part of the dissolution time curve. It is often expressed as amount of drug dissolved per time
`and surface area unit (G), e.g., mg/cm2·s, by dividing the rate by the surface area of the disc.
`This dissolution rate is specific for the rotational speed (␻) of the disc and is linearily related
`to the square root of the rotational speed of the disc according to hydrodynamic therories that
`have been experimentally verified (Levich 1962). Thus, if experiments are performed at sev-
`eral rotational speeds, and the dissolution rate at each speed is plotted versus the square root
`of the rotational speed, a linear relationship should be obtained. It should be noted that this
`determination of dissolution rate is still dependent on other experimental hydrodynamic
`conditions, such as positioning of the disc, shape of the vessel and viscosity. An equation has
`therefore been derived that allows for determination of an “intrinsic dissolution rate” (k1) that
`is independent of the drug diffusion in the boundary layer (Niklasson and Magnusson 1985);
`1
`k
`¢
`=
`0 5
`¥w .
`G k
`
`R
`
`(2)
`
`+
`
`1 1
`
`
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 103
`
`Biopharmaceutical Support in Candidate Drug Selection
`
`103
`
`Figure 4.2a The rotating disc method: the disc holder and the compressed disc.
`
`Figure 4.2b The rotating disc method: experimental set-up for the rotating disc.
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 104
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`104
`
`Pharmaceutical Preformulation and Formulation
`
`where k¢ is a proportionality constant. The rotating disc must be mounted eccentrically at a
`certain distance (R) from the center of the stirring rod to perform this evaluation. A plot is
`made between 1/G and 1/(R ⫻ ␻0.5) at different agitation rates, which should yield a straight
`line. The reciprocal of the “intrinsic dissolution rate” (1/k1) is determined by extrapolating the
`line to the y axis. If G is determined at different speeds, and laminar flow along the disc can
`be assumed, other theoretical evaluations can be made of the data, such as determination of
`the diffusion coefficient of the drug in the boundary layer around the solid particles and the
`thickness of the diffusion boundary layer (Levich 1962).
`The main merits of the rotating disc apparatus are the well-defined hydrodynamic con-
`ditions and constant surface area. These reduce the risk of artefacts in dissolution rate deter-
`minations caused by non-ideal test conditions. Furthermore, it is possible to determine an
`intrinsic dissolution rate and to perform other mechanistic evaluations of the dissolution
`process. The main limitation of the method is that it is not suitable for drugs that form frag-
`ile or porous discs, since it is not possible to maintain a constant surface area.
`The drug dissolution rate of powder may be determined by methods such as in a beaker
`with appropriate agitation, as described in the pharmacopoeial methods. The dissolution
`rate determined by such approaches will be method dependent, and it will not be possible
`to derive an intrinsic value of the dissolution rate. The main reason for using this type of
`experimental approach can be understood when the effect of the drug particle size must be
`considered. Experimental errors and uncontrollable variations may occur for hydrophobic
`drugs due to agglomeration in the test medium or due to floating. The use of a wetting agent
`in the test medium (such as a surfactant in concentrations well below the critical micelle con-
`centration [CMC]), may be needed to avoid such undesired effects.
`
`Biopharmaceutical Interpretation of Dissolution/Solubility Data
`
`It is desirable to predict the influence of drug dissolution on oral absorption based on meas-
`urements of dissolution or solubility, both before the selection of a candidate drug, in order
`to obtain a drug molecule with acceptable properties, and in the preformulation phase, to de-
`termine the need for solubility-enhancing formulation principles. The primary variable for
`judgements of in vivo absorption is the dissolution rate rather than the solubility. Drug disso-
`lution will limit the bioavailability when the dissolution rate is too slow to provide complete
`dissolution in the part of the intestine where it can be absorbed. In addition, the drug con-
`centration in the intestinal fluids will be far below the saturation solubility, under the as-
`sumption that “sink conditions” in the GI tract will be obtained due to absorption of the drug.
`However, most often, solubility data are more readily available than dissolution rates for a
`drug candidate, especially in early phases when the amount of drug available does not allow
`for accurate dissolution rate determinations. Predictions of in vivo effects on absorption
`caused by poor dissolution must thus often be made on the basis of solubility data rather than
`dissolution rate. This can theoretically be justified by the direct proportionality between dis-
`solution rate and solubility under “sink conditions” according to equation 1. A list of proposed
`criteria to be used to avoid a reduction in absorption caused by poor dissolution is given in
`Table 4.2. These criteria are discussed in further detail in this chapter. A solubility in water of
`ⱖ 10 mg/mL in pH range 1–7 has been proposed as an acceptable limit to avoid absorption
`problems, while another suggestion is that drugs with water solubilities ⬍0.1 mg/mL often
`lead to dissolution limitations to absorption (Kaplan 1972; Hörter and Dressman 1997). It
`should be noted that these limits may be conservative, especially in the context of screening
`and selection for candidate drugs. For example, a drug with much lower solubility, such as
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 105
`
`Biopharmaceutical Support in Candidate Drug Selection
`
`105
`
`Table 4.2
`Proposed limits of drug dissolution on solubility to avoid absorption problems.
`Factor
`Limit
`Reference
`
`Solubility in pH 1–7
`Solubility in pH 1–8 and dose
`
`Water solubility
`
`Dissolution rate in pH 1–7
`
`⬎10 mg/mL at all pH
`Complete dose dissolved in
`250 mL at all pH
`⬎0.1 mg/mL
`
`⬎1 mg/min/cm2 (0.1–1 mg/nm/cm2
`borderline) at all pH
`
`Kaplan (1972)
`Amidon et al. (1995)
`
`Hörter and
`Dressman (1997)
`Kaplan (1972)
`
`felodipine (0.001 mg/mL), provides complete absorption when administered in an appropri-
`ate solid dosage form (Wingstrand et al. 1990). This may be explained both by successful ap-
`plication of dissolution-enhancing formulation principles and by more favourable drug
`solubility in vivo owing to the presence of solubilising agents such as bile acids.
`Another model for biopharmaceutical interpretation based on solubility data is found in
`the biopharmaceutical classification system (BCS) (Amidon et al. 1995). Four different classes
`of drugs have been identified, based on drug solubility and permeability as outlined in Table
`4.3. If the administered dose is completely dissolved in the fluids in the stomach, which is as-
`sumed to be 250 mL (50 mL basal level in stomach plus administration of the solid dose with
`200 mL of water), the drug is classified as a “high solubility drug”. Such good solubility should
`be obtained within a range of pH 1–8 to cover all possible conditions in a patient and exclude
`the risk of precipitation in the small intestine due to the generally higher pH there than in the
`stomach. Drug absorption is expected to be independent of drug dissolution for drugs that
`fulfil this requirement, since the total amount of the drug will be in solution before entering
`the major absorptive area in the small intestine, and the rate of absorption will be determined
`by the gastric emptying of fluids. Thus, this model also provides a very conservative approach
`for judgements of dissolution-limited absorption. However, “highly soluble drugs” are advan-
`tageous in pharmaceutical development since no dissolution-enhancing principles are
`
`Class
`
`I
`II
`III
`IV
`
`Table 4.3
`Biopharmaceutical classification system.
`Solubility
`
`High
`Low
`High
`Low
`
`Permeability
`
`High
`High
`Low
`Low
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 106
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`106
`
`Pharmaceutical Preformulation and Formulation
`
`needed, and process parameters that could affect drug particle form and size are generally not
`critical formulation factors. Furthermore, if certain other criteria are met, in addition to
`favourable solubility, regulatory advantages can be gained. Bioequivalence studies for bridg-
`ing between different versions of clinical trial material and/or of a marketed product can be
`replaced by much more rapid and cheaper in vitro dissolution testing (Guidance for Industry,
`FDA 1999; Note for Guidance on Investigation, EMEA 1998).
`The assumption of “sink condition” in vivo is valid in most cases when the permeability
`of the drug over the intestinal wall is fast, which is a common characteristic of lipophilic,
`poorly soluble compounds. However, if such a drug is given at a high dose in relation to the
`solubility, Ct (see equation 1) may become significant even if the permeation rate through the
`gut wall is high. If the drug concentration is close to Cs (see equation 1) in the intestine, the
`primary substance-related determinants for absorption are the administered dose and Cs
`rather than the dissolution rate. It is important to identify such a situation, since it can be ex-
`pected that the dissolution rate-enhancing formulation principle will not provide any bene-
`fits and that higher doses will provide only a small increase in the amount of absorbed drug.
`As a rough estimate for a high permeability drug, it has been proposed that this situation can
`occur when the relationship between the dose (mg) and the solubility (mg/mL) exceeds a fac-
`tor of 5,000 if a dissolution volume of 250 mL is assumed (Amidon 1996). For example, if the
`solubility is 0.01 mg/mL, this situation will be approached if doses of about 50 mg or more are
`administered. It should, however, be realised that this diagnostic tool is based on theoretical
`simulations rather than in vivo data. For example, physiological factors that might affect the
`saturation solubility are neglected (described in more detail below).
`In order to predict the fraction absorbed (Fa) in a more quantitative manner, factors
`other than dissolution, solubility or dose must be taken into account, such as regional per-
`meability, degradation in the GI lumen and transit times. Several algorithms with varying de-
`grees of sophistication have been developed that integrate the dissolution or solubility with
`other factors. A more detailed description is beyond the scope of this chapter, but a compre-
`hensive review has been published by Yu et al. (1996). Computer programmes based on such
`algorithms are also commercially available and permit simulations to identify whether the ab-
`sorption is limited by dissolution or solubility (Gastroplus™, Simulations Plus Inc, Lancaster,
`Calif., USA). As an example, Figure 4.3 shows simulations performed to investigate the de-
`pendence of dose, solubility and particle radius on the Fa for an aprotic, high-permeability
`drug.
`
`Physiological Aspects of Dissolution and Solubility Test Conditions
`
`The dissolution of a drug in the gut lumen will depend on luminal conditions, e.g., pH of the
`luminal fluid, volume available, lipids and bile acids and the hydrodynamic conditions pro-
`duced from the GI peristaltic movements of the luminal content toward the lower bowel. Such
`physiological factors influence drug dissolution by controlling the different variables in equa-
`tion 1 that describe the dissolution rate. This is summarised in Table 4.4 adapted from Dress-
`man et al. (1998).
`The test media used for determining solubility and dissolution should therefore ideally
`reflect the in vivo situation. The most relevant factors to be considered from an in vivo per-
`spective are
`
`•
`
`•
`
`pH (for proteolytic drugs),
`
`ionic strength and composition,
`
`

`

`1408_Chapter 04II 6/10/03 10:34 AM Page 107
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`Biopharmaceutical Support in Candidate Drug Selection
`
`107
`
`Figure 4.3 Simulations of fraction of drug absorbed after oral administration for a high-
`permeability drug (Peff = 4.5 ⫻ 10–4 cm/s) for doses 1–100 mg, water solubilities
`0.1–10 g/mL and radius of drug particles 0.6–60 ␮m. During variations of one variable,
`the others are held constant at the midpoint level (dose 10 mg, solubility 1 ␮g/mL and
`particle radius 6 ␮m).
`
`particle
`radius
`
`dose
`
`solubility
`
`Percent Drugs Absd.
`
`
`
`1
`Dose (mg)
`Solubility ((cid:181)g/mL) 0.1
`Particle radius ((cid:181)m) 0.6
`
`10
`1
`6
`
`100
`10
`60
`
`Table 4.4
`Physicochemical and physiological parameters important to
`drug dissolution in the gastro-intestinal tract.
`Physicochemical
`Parameter
`
`Physiological Parameter
`
`Factor
`
`Surface area of drug (A)
`
`Particle size, wettability
`
`Molecular size
`
`Hydrophilicity, crystal
`structure, solubilisation
`
`Diffusivity of drug (D)
`Boundary layer thickness (h)
`Solubility (Cs)
`
`Amount of drug already
`dissolved (Ct)
`Volume of solvent
`available (Ct)
`
`Surfactants in gastric juice
`and bile
`Viscosity of lumenal contents
`Motility patterns and flow rate
`pH, buffer capacity, bile,
`food components
`Permeability
`
`