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.
Patricia Van Arnum
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.