Seeking Solutions in Solid-State Chemistry

Oct 01, 2012

Patricia Van Arnum
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 crystallisation 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, hot-melt extrusion (HME), spray-congealing and inclusion-complex generation. Pharmaceutical Technology Europe discussed these issues with Colin Minchom, vice president, Particle Design Business Unit, at Hovione.


PTE: Under what type of situations would cocrystallisation 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.

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 favoured approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionisable 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, micronised and nanosized crystals and inclusion complexes.

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

Minchom: Where milling techniques can be thought of as top-down sizing techniques, controlled crystallisation is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallisation 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, crystallisation may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.

The kinetics of crystallisation (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.

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