Solubilizing the Insoluble - Pharmaceutical Technology

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PharmTech Europe

Solubilizing the Insoluble
An analysis of the approaches and tools used to tackle the problem of poorly soluble drugs.

Pharmaceutical Technology
pp. 50-56

Solid dispersions/solid solutions

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dispersed in an inert matrix. In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solutions, refers to the case in which drug–polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutical polymers are used to create this matrix. Polymer selection is based on many factors, including physicochemical (e.g., drug–polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints (4).

Solid dispersions may be made through mechanical activation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies, Austin, TX), a fusion-processing technology. The solid-dispersion components consist of the API, the polymer, plasticizers, stabilizers, and other agents, explains Asgarzadeh. Various polymers may be used in solid dispersions. These include methylacrylate polymers, polyvinyl acetate, polyvinylpyrrolidone, copovidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and cellulose derivatives (e.g., hypromellose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose).

When developing solid-dispersion formulations of poorly soluble APIs, one may compare the API functional groups with the polymer functional groups, compare the API solubility parameters with polymer–solubility parameters, and analyze the expected permeability of the API to determine which polymers to evaluate for solid-dispersion technology (4). Additional factors such as the API permeability window, polymer supply, polymer toxicology, physical-product characteristics, and processing yields are also factors that have to be considered during product development (5).

The pharmaceutical plasticizers used in hot-melt extrusion may be used for various applications, explains Asgarzadeh. They can be used to reduce glass-transition temperature and melt viscosity, to lower processing temperature, to improve flexibility, and to improve extrudate surface appearance (i.e., smoothness). Examples of plasticizers that may be used in these applications are triethyl citrate, low-molecular weight polyethylene glycols, dibutyl sebacate, propylene glycol, diethyl phthalate, dibutyl phthalate, and glycerol monostearate.

As with any pharmaceutical formulation, a key consideration in the development of a hot-melt extrusion formulation is to evaluate whether the API, the polymer, and other ingredients will be effective in a given formulation. "By predicting compatibility and miscibility, it can be checked if the drug, polymer, or other ingredients fit together," says Asgarzadeh. "This prediction can reduce the number of feasibility experiments, thereby saving time, the amount of API used in studies, and the cost of such studies."

Predictive modeling. Solubility parameters can predict possible interactions between a drug molecule and the polymers used in a hot-melt extrusion application. Miscibility can be evaluated quantitatively and qualitatively. A qualitative evaluation excludes hydrogen-bonding capability. A quantitative estimation involves estimating the solubility parameter, which is a function of non-hydrogen-bonded parameters and hydrogen-bonded parameters. "For non-hydrogen-bonded parameters, the question being asked is: Will dispersive forces lead to an one-phase system?" says Asgarzadeh. "For hydrogen-bonded parameters, the question being asked is: Are hydrogen bonds involved to avoid crystallization?"

Evonik has developed a system, Melt Extrusion Modeling and Formulation Information System (MEMFIS), as a predictive modeling tool in developing a hot-melt extrusion formulation. MEMFIS helps in selecting initial formulations with no API consumption, using mathematical models and algorithms based on solubility parameter theories (i.e., hydrogen bonding and polar and dispersive forces). MEMFIS uses chemical structures, solubility parameters, physicochemical properties, and a myriad of processing conditions to suggest initial formulation components and process settings for a hot-melt extrusion formulation.

In terms of miscibility estimation, for example, MEMFIS evaluates which excipients have higher potential to form a solid solution by assessing the drug miscibility of a given excipient in comparison to other excipients. The qualitative method, (i.e., which excludes hydrogen-bonding capability in the evaluation) considers the drug miscibility with an excipient in comparison to other excipients to make the determination of whether one excipient is more or less miscible. Only dispersive interactions are considered. Qualitative-only methods may lead to the exclusion of valuable excipients from the screening studies that could potentially form strong hydrogen bonds with the APIs.

In the quantitative evaluation in the MEMFIS, which is a deeper analysis, in addition to polar and dispersive interactions, the specific possible hydrogen-bonding interactions are investigated at a molecular level to derive a quantitative expectation in terms of drug–excipient miscibility in a binary system. In this quantitative assessment, additional specific hydrogen-bonding capability is considered. This involves considering polymers from a monomer perspective (i.e., meaning the composition of the polymer) and specifying the type of hydrogen bonding that could be involved and its impact on the solubility parameters. "Solubility-parameter estimation and molecular-interaction considerations are powerful tools in estimating first formulations in solid-dispersion product development," says Asgarzadeh. "High- throughput screening is accomplished based upon molecular structure, intra- and inter-molecular bonding, and their impact on solubility parameters."

Commercial examples. Several commercial products use solid solutions or solid dispersions. One example is a solid dispersion of crystalline griseofulvin in polyethylene glycols (gris-PEG), which cut the crystalline 500-mg dose in half while maintaining plasma concentrations. Another example is the antiemetic Cesamet (nabilone) (Valeant Pharmaceuticals, Costa Mesa, CA), which contains a solid dispersion of nabilone in polyvinylpyrrolidone. Solid solutions of lopinavir and ritonavir in polyvinylpyrrolidone–vinyl acetate copolymer enabled a reformulation of Kaletra (Abbott Laboratories, Abbott Park, IL). Sporanox (Janssen Pharmaceutica, Titusville, NJ) is a solid dispersion of itraconazole in hypromellose that has been layered onto sugar spheres. The nonnucleoside reverse transcriptase inhibitor Intelence (Tibotec, Yardley, PA), is an amorphous, spray-dried solid dispersion of etravirine, hypromellose, and microcrystalline cellulose (4).


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