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
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.
IMAGES ETC LTD/GETTY IMAGES
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.