Seeking Solutions in Solid-State Chemistry

The physical form of an API is important in formulation development for resolving issues in bioavailability and solubility. Particle-engineering technologies can be applied in various ways: crystal design for controlling crystallization and producing cocrystals; particle-size reduction, achieved through jet-milling, wet polishing and nanoparticle generation; and amorphous solid dispersions, produced by several approaches, such as spray-drying (including as inclusion complexes), hot-melt extrusion (HME), and spray-congealing. Pharmaceutical Technology discussed these issues with Colin Minchom, vice president, of the Particle Design Business Unit at Hovione.

Patricia Van Arnum

Crystallization

PharmTech: Under what type of situations would crystallization be used? How does it facilitate the delivery of poorly soluble drugs?

Minchom: Interest in cocrystals has increased in recent years, and the recent FDA guidance on a proposed classification of cocrystals has prompted further discussion and counter proposals from the industry. The proposed US FDA classification of cocrystals as crystalline materials containing two or more molecules in the same crystal lattice is limited but can serve as a starting point for discussion.

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The addition of a cocrystal former into the crystalline structure of the API changes its physical and chemical properties. It is possible, in some cases, to improve bioavailability to adequate levels while preserving the stability of a crystalline form. For APIs with low glass-transition temperatures, a cocrystal may be favoured over the amorphous form. As such, the use of a cocrystal may be an attractive platform to overcome the solubility limitations of Biopharmaceutics Classification System Class II and Class IV drugs.

Cocrystal formation is a favored approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionizable groups, and for which salt formation is not possible, or for where the physical properties of the salts formed are not desirable. Solvates and hydrates are well-accepted crystal forms. In many ways, a cocrystal can be thought of as a solvate, but one whose components are solid at room temperature. The cocrystal will form if the resulting crystal is thermodynamically more stable than the components. Resulting cocrystal properties are dependent upon many factors, including the starting properties of the API, the physical properties of the co-former and the mechanism by which the cocrystal is formed. To increase the probability of success, we [Hovione] recommend that at early-development stages to test other proven platforms, such as solid dispersions, micronized and nanosized crystals and inclusion complexes.

Applying acoustic levitation for elucidation of amorphous material

PharmTech: Controlling nucleation during crystallization is an important task. What are the mechanisms for controlling crystallization?

Minchom: Where milling techniques can be thought of as top-down sizing techniques, controlled crystallization is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallization process are twofold. On the one hand, the aim is to isolate the API in the right crystal form, typically a polymorph that provides the required level of exposure and stability. On the other hand, crystallization may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.

The kinetics of crystallization (nucleation and crystal growth rates) are driven by the imposed supersaturation levels. The degree of supersaturation, temperature ramp, mixing, filtration and final drying process all contribute to the final particle-size distribution. Moreover, the relative importance of each factor can change at each scale.

Particle-size reduction

PharmTech:What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing, and nanoparticle generation?

Minchom: Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical behavior. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such as crystal hardness, morphology, and original crystal size, as well as the size-reduction method and energy applied. Jet-milling and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result from jet-milling while a higher level of crystallinity is maintained with wet polishing.

Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating techniques), but they are more aggressive, less reproducible, and more limited in terms of the achievable size reduction.

Amorphous solid dispersions

PharmTech: What factors determine which method (i.e., spray-drying, HME, spray-congealing, and inclusion-complex generation) to use to produce the amorphous solid dispersion?

Minchom: Amorphous solid dispersions represent a tremendous opportunity for solubility enhancement of oral drugs. The resulting supersaturation levels (and hence bioavailability) and the physical stability of the final dosage form, however, depend on the manufacturing method applied. Many approaches are available to generate amorphous solid dispersions.

Spray-drying, being a solvent method, is the most versatile technique to obtain solid dispersions due to its gentle process conditions and much wider formulation options. Spray-drying is a technology that works well in nearly every compound. Another advantage of spray-drying is that it can be effectively operated using much smaller quantities of drug substance, thereby making it the most cost-effective option during early-stage development.

Melt methods, such as HME and spray-congealing, on the other hand, are more cost effective at the larger scale manufacturing and have the additional advantage of being solvent-free techniques. To use these methods, however, the compound needs to be soluble in the polymer/matrix and physically stable complexes need to be created. These methods are also limited to drug substances that can sustain relatively high heat loads. All these techniques are relatively well-established within the pharmaceutical industry, although spray-drying is a step ahead in terms of maturity.

Although challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form self emulsifying drug-delivery systems (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as well as the polymers commonly used in spray-dried amorphous solid dispersions.

Patricia Van Arnum is executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com twitter@PharmTechVArnum.