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
Under what type of situations would crystallization be used? How does it facilitate the delivery of poorly soluble drugs?
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
Controlling nucleation during crystallization is an important task. What are the mechanisms for controlling crystallization?
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.