Extrusion Processing of Pharmaceuticals
5.1 Introduction
5.1.2 Solubility/Dissolution Enhancement by Solid Dispersions
Out of all the applications mentioned, by far the most prominent use of HME is the dispersion of insoluble or poorly soluble APIs in a hydrophilic polymer matrix, with the purpose to enhance their solubility and dissolution in general. Over the recent years, investigation of the applicability of polymers in various pharmaceuti-cal formulation processes has gained a great deal of attention from researchers and formulation developers, since the number of insoluble or poorly soluble APIs has increased. An increasingly large percentage of new drug candidates consist of low aqueous solubility compounds, an increase that has been attributed to the applica-tion of high throughput screening methods, and the use of solvents like DMSO or PEG in the drug discovery process [17]. In order to classify APIs according to their aqueous solubility and membrane permeability (properties that determine their bio-availability), the Biopharmaceutics Classification System (BCS) has been proposed [18] (Figure 5.1).
APIs are categorized as having “High” or “Low” solubility and permeability, and four classes can be constructed on the basis of combinations of those two solubility and permeability levels. High or low solubility is defined as “the number of glasses of water required to dissolve a tablet in its highest dose” [17], which is mathematically expressed by the so-called “Dose Number,” Do, which represents the ratio of the highest drug dose in an administered volume of 250 ml, to the drug’s aqueous saturation solubility.
Figure 5.1 The Biopharmaceutics Classification System. Reprinted with permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery 7, 255-270 (February 2008).
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Generally, a Do<1 indicates high solubility, while Do>1 is an indication of low solubility APIs. Permeability is expressed as logP or ClogP, which represents the partition coef-ficient of a substance in its neutral state between n-octanol and water. Metoprolol, with a logP of 1.72 and 95% absorption in the gastrointestinal tract, has been chosen as the reference standard that distinguishes between high and low permeability compounds.
APIs with logP>1.72 are classified as high permeability, while those with logP<1.72 are considered as low permeability drugs.
The increasing number of new drug candidates and eventually APIs that fall under Class II of the BCS, has generated a need for the development of novel solid forms of the drug with enhanced aqueous solubility, which is because the solubility of a substance depends primarily on its solid form rather than on its molecular structure [19]. In order to overcome the low solubility barrier in drug formulation, various physical methods are applied for the solubility enhancement of APIs, including crystal form modifica-tion, particle size reducmodifica-tion, inclusion in cyclodextrins, and formation of binary (or multicomponent) composite phases [20], most commonly, dispersions of the API in amorphous or crystalline state, into a polymer matrix. Most of the aforementioned methods are subject to limitations and therefore have not found universal applicability.
Modification of the crystal form involves the risk of unanticipated polymorphic transi-tions; particle size reduction is usually achieved by means of milling, which results in the mechanical activation of crystalline particles and entails the risk of formation of undesirable solid phases, while formation of inclusion compounds with cyclodextrins is limited only to molecules of small to moderate size [20]. Therefore, the formation of binary composite phases by HME appears as the most attractive, advantageous, and feasible alternative, and that’s where polymers find prominent use in the formulation process.
The physicochemical character of the composite phases depends on the crystallin-ity of the polymeric carrier and the potential for interaction between drug and poly-mer. As described earlier, during the HME process a drug is mixed with a polymeric carrier under the influence of high temperature (typically above the polymer’s glass transition or melting temperature) and shear forces. Under these conditions, the drug is either dissolved, or dispersed in the softened polymer, resulting in loss of crystal-linity and amorphization. After equilibration at ambient conditions, depending on their chemical structure, the drug and polymer can crystallize or remain amorphous in the final extrudate. Based on the possible combinations of drug and polymer phys-ical states (crystalline or amorphous), the following types of solid dispersions can be formed:
a. Crystalline drug – crystalline polymer: the drug forms a solid suspen-sion in the polymer matrix. Dissolution enhancement is mostly due to the small particle size of the dispersed drug microcrystals, resulting in an increase of the surface area available for dissolution, and improved wetting of drug microcrystals. Eutectic mixtures constitute a special case of crystalline solid suspensions, where the drug forms a microlayered structure in the polymer matrix.
Polymers as Formulation Excipients for Hot-Melt 125 b. Amorphous drug – amorphous polymer: both drug and polymer assume
the amorphous state, rendering the extrudate highly soluble, due to the metastability of both phases. The drug can be dispersed in the form of amorphous microparticles (amorphous suspension), or it can be molec-ularly dispersed to form an amorphous solid solution [21].
c. Crystalline drug – amorphous polymer: the drug either crystallizes at the end of the HME process or remains crystalline throughout. Dissolution enhancement is mainly achieved due to the small particle size of the drug, but also to the improved wetting, facilitated by the fast-dissolving amorphous polymeric carrier.
d. Amorphous drug – crystalline polymer: The drug may be dispersed in the form of amorphous microparticles or form a classical (substitutional or interstitial) solid solution [21], where it is molecularly dispersed.
Dissolution enhancement is high and is controlled by the ability of the carrier to stabilize the amorphous state of the drug.
Generally, two mechanisms describing the dissolution of drugs from HME product have been proposed [22] that involve either polymeric carrier or drug controlled release (Figure 5.2). More specifically, as the composite phase comes into contact with the dissolution medium, the polymer is hydrated and forms a gel layer.
Depending on the drug’s solubility in the hydrated polymer layer, two cases can be distinguished:
a. The drug is highly soluble in the hydrated polymer layer: the drug will dissolve into that layer subsequently diffusing through it into the dissolution medium (Figure 5.2, case a). In this case dissolution rate is limited by the viscosity of the hydrated layer. For hydrophilic polymers that form low viscosity layers, a significant dissolution enhancement can be achieved, and in addition, the interaction between drug and polymer may prevent the formation of a stable phase due to the high local super-saturation at the solid-liquid interface.
b. The drug’s solubility in the hydrated polymer layer is limited: the drug particles will be released intact into the dissolution medium. Dissolution rate is independent of the polymer’s properties but rather depends on the drug solid state (physical form, crystallinity or absence of it) and particle size, which defines the area available for dissolution. In the case of an amorphous solid solution type of composite phase, dissolution enhancement is great. However it has been recently argued that the final solubility advantage may be compromised by supersaturation genera-tion rate effects [23], and may not be as high as theoretically predicted.
In order to explain the notable dissolution enhancement achieved by the dispersion of a poorly soluble drug into a hydrophilic polymer matrix, the “spring and parachute”
model (Figure 5.3) has been proposed [17,24]. According to this model, the metastable
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amorphous phase provides instantaneous supersaturation (the spring) due to its high free energy. Peak solubility can be maintained for a sufficient amount of time, due to precipitation inhibition achieved by the polymer, as well as the stepwise crystallization of the drug to its higher soluble metastable polymorphs (the parachute), before it forms the poorly soluble stable form, according to Ostwald’s law of stages [17].
Figure 5.2 Drug dissolution process from suspension type solid dispersions: (a) polymeric carrier-controlled dissolution: polymer dissolution precedes that of the drug (large spheres), and the drug subsequently partially dissolves (small spheres) into the hydrated layer (shaded area) before release into the dissolution medium, and (b) drug-controlled dissolution whereby drug release precedes dissolution of the carrier and is essentially independent of it. It should be noted that the same mechanisms apply in the case of amorphous solid solution type composite phases. Reprinted with permission from [22], Copyright 2002 Elsevier.
Figure 5.3 Schematic representation of the spring and parachute model: high supersaturation relevant to the stable form of the drug is achieved by the use of the amorphous phase (the spring), while desupersaturation is retarded when favorable interactions with the hydrophilic polymer inhibit crystallization or facilitate the growth of metastable forms (the parachute). Reprinted with permission from [24], Copyright 2007 Wiley.
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