Effective Formulation Development Strategies for Poorly Soluble Active Pharmaceutical Ingredients (APIs)


One of the least desired outcomes of utilizing combinatorial and high throughput chemistry has been a marked increase in poorly soluble drug candidates [1]. The number of poorly soluble new drugs entering development has been estimated to be anywhere from 40% to 70% [2]. Most companies are increasingly focusing their attention on the bio-pharmaceutics properties of their drug candidates (particularly solubility and permeability) to understand the impact on clinical exposure. Butler and Dressman [3] advocated a Development Classification System (DCS) that builds upon the pioneering work of the Biopharmaceutical Classification System (BCS) [4).

The DCS system utilizes bio-relevant solubility e.g. FESSIF/FASSIF (fed state/fasted state simulated intestinal fluid), permeability and predicted clinical dose to model novel drug candidates. The DCS system also splits BCS class II into two sub-divisions (DCS IIa and IIb). The former encompasses molecules that typically show dissolution rate limited absorption. In contrast, the latter (IIb) show solubility rate limited absorption. Knowledge of formulation strategies for similar compounds in the same ‘DCS-space’ to the candidate allows insight into the optimum formulation approach.

Formulation Strategies for DCS Class IIa Compounds

For dissolution rate limited absorption (DCS IIa) the formulation strategy is predicated on increasing the rate of solubility (dissolution rate), which is described by the Noyes-Whiney equation [5]:

dC/dt= D/h x S (Cs – Ct)           (1)

Under sink conditions, Cs >> C,
and equation 1 becomes:

dC/dt= (D x S x Cs)/h                (2)

where dC/dt is the dissolution rate, D is the diffusion coefficient of the drug, h is the thickness of the diffusion layer, S is the surface area of the dissolving solid, Cs and Ct are the aqueous solubility and the concentration of the drug at time t, respectively.

Table 1 - Advantages and Disadvantages of Salt Formation.

Salt Formation Strategies

Salt formation is the most common and effective process for increasing both solubility (Cs) and dissolution rate (dC/dt) for acid and basic drugs. The salt form may well impact on the wettability, and thereby h. Salt formation can increase solubility several hundred fold which has a significant effect on the dissolution rate [6]. The advantages and disadvantages of salt formation are given in Table 1.

Table 2 - Advantages and Disadvantages of Size Reduction.

Size Reduction Strategies

Size reduction strategies (either micronization or nanosizing; the latter is also called wet bead milling) can enhance the effective surface area (S) of a drug [9]. A 120-nm suspension of MK-0869 enhanced the surface area by 42x compared to the standard 5μm suspension [10]. In addition, the polymeric stabilizers present within the formulations can improve h [11]. It has been reported that there can also be some increase in solubility (Cs) of the API, based on the Friendlich-Ostwald equation by approximately 10-15x [12, 9]. The advantages and disadvantages of this approach are given in Table 2.

Use of Surfactants

Surfactants can have several functional roles; (i) enhance API solubilization, (ii) enhance API wettability (iii) enhance API dissolution and (iv) reduce in vivo API precipitation [13, 14]. The mechanisms of surfactant solubilization have been extensively evaluated [15]. These approaches are attractive as they are aligned with standard tabletting processes, are easily scalable and are very cost effective [13, 16]. Care is required with the sourcing and control of surfactants as differences can impact on the critical micelle concentration (CMC), which impacts on the solubility rate [14].

Formulation Strategies for DCS Class IIB Compounds

The main formulation strategy for DCS class IIB compounds is to increase Cs either by using complexes e.g. cyclodextrins, delivery of APIpre-solubilized API e.g. hydrophilic or lipophilic solvents (softgels) or by using amorphous stabilized approaches.

Table 3 - Advantages and Disadvantages of Cyclodextrins.

Use of Cyclodextrins

Cyclodextrins (CyDs) are functional excipients that form dynamic inclusion complexes in solution with APIs. Typically the substituted β-CyDs are used in formulation, e.g. HPβCyD and SBEβCyDs, because of their very high water solubility (> 500mg/ml) [17]. Typically, the hydrophobic API resides within the hydrophobic torus and the very high aqueous solubility of the complex is imparted by the external hydrophilic cyclic oligosaccharides. CyDs typically solubilize APIs as a function of their concentration. Under in vivo physiological conditions they are also released in a similar fashion (via dilution of the complex), ensuring that precipitation is unlikely. In contrast, co-solvents solubilize APIs as a function of the logarithm of the API concentration, and hence precipitation is likely [17]. In addition, it is also possible for CyDs to form non-inclusion complexes, with H-bonded interaction between the external face of the CyD torus and the API [18]. Small quantities of water soluble polymers e.g. polyvinylpyrollidone (PVP) can enhance the efficiency of the complexation process facilitating reduction of the levels of CyD required [19].

The advantages and disadvantages of cyclodextrins are given in Table 3.

Table 4 - Advantages and Disadvantages of Hydrophilic and Lipidic Solvents.

Use of Hydrophilic and Lipidic Solvents

Lipid based formulations have been shown to enhance oral absorption of lipophilic drugs and mitigate any potential food effects [21]. This approach is successful as the drug is already fully solubilized in lipidic solvents before being administered into the body (higher Cs). This is particularly appropriate for compounds with high Log P [22]. In recent years the utility of self-emulsifying drug delivery systems (SEDDS) and the related SMEDDS (self-microemulsifying drug delivery systems) have been advocated and successfully commercialized e.g. Neoral cyclosporine (SMEDDS) [23]. Hydrophilic vehicles e.g. polythene gycols (PEGs), poloxamers, etc are ideal solvents as they have good solvating properties and are miscible with water at all levels. However, one of the major downsides to such approaches is the greater potential for precipitation on contact with GI media. [23]. The advantages and disadvantages of this approach are given in Table 4.

Table 5 - Comparison of different amorphous stabilized approaches

Use of Amorphous Stabilized Approaches

Amorphous stabilized approaches increase solubility (Cs) by overcoming crystal lattice energy to yield a non-crystalline, amorphous API; which is thermodynamically metastable compared to the crystalline state. This can significantly enhance both solubility and bioavailability. The biggest challenges however remain chemical and physical stability. The amorphous state can be viewed as a pseudo-solution state demonstrating greater chemical reactivity [25]. This greater reactivity is reflected in reduced stability and shelf-life.

The high molecular mobility of water, acting as a plasticizer, can increase both chemical reactivity and anneal the amorphous material, transforming it into its crystalline counterpart – with resultant loss in bio-enhancement. One of the greatest challenges is that predictive assessment of physical stability still remains in its infancy. This is reflected in two key areas. Firstly, the sensitivity of supporting analytical methodologies e.g. X-ray, thermal approaches; capable of detecting low levels of crystalline material in the presence of amorphous material, are generally poor. Typically sensitivities are 1-5% (cf. chemical stability where 10ppm is not uncommon). Secondly, ICH stability storage conditions aimed at predicting real time stability based on elevated temperature/humidity storage (based on the Arrhenius kinetics) are less relevant to systems that can change phase (amorphous to crystalline) as a consequence of the presence of water. Hence it is difficult to accurately predict shelf-lives based on stress storage/testing.

The most attractive approaches for the manufacture of solid amorphous dispersions are hot melt extrusion, spray drying, freeze drying, co-evaporation or co-precipitation and roller mixing or co-milling; with the first three techniques predominating in the literature. Melt extrusion reflects possibly the best approach and has been used in oral, topical and parental indications [26].

Spray drying has been widely utilized, particularly to produce respirable particles by ‘first intent’ for pulmonary delivery [27]. In this case the solubility is often enhanced using either non-aqueous solvents or super critical fluid assisted nebulization.

Freeze drying (or lyophilization) is not typically associated with low solubility applications, rather it is usually utilized for bio-pharmaceuticals. However, lyophilization is still attracting interest. DiNunzio et al [28] recently reported its application to itraconazole. The API was dissolved in non-aqueous media, i.e. 1,4-dioxane, polymers e.g. cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP) were added before ultra-rapid cooling was utilized to produced amorphous solid dispersions. The authors indicated that enhanced bioavailability was correlated with supersaturation and that polymers capable of addressing precipitation were required. Table 5 compares the three most common amorphous stabilization approaches.


In silico modeling based on bio-relevant solubility, permeability and anticipated clinical dose allows for educated formulation design. This APIarticle has explored different formulation strategies based on rationale application of the DCS approach. The use of these approaches can maximize clinical exposure, save resource and expenditure whilst minimizing development timelines.


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David P. Elder has 33-years experience in the pharmaceutical industry. He is a director in the SCINOVO group at GSK. He has a PhD from Edinburgh University, UK. He is a member of the British Pharmacopoeia Commission and an FRSC. He has written and lectured worldwide on bio-enhancing formulation strategies.

This article was printed in the March/April 2011 issue of Pharmaceutical Outsourcing, Volume 12, Issue 2. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.

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