Control of the Particle Properties of a Drug Substance by Crystallization Engineering and the Effect on Drug Product Formulation

Abstract

A study of the process-property-performance relationship of a Bristol-Myers Squibb drug substance led to successful development of crystallization and drying processes that produce crystals with desired and consistent physical properties. A controlled crystallization technique was developed to obtain well-defined, large crystals with a narrow particle size distribution. This crystallization process provided a less compressible filter cake for effective cake washing and deliquoring and afforded an easily dried product with desired powder properties. To preserve the quality of the crystals during drying, a drying protocol using low shear agitation was developed. This protocol prevented crystal attrition during drying, which was shown to adversely affect the formulation process and, thus, drug product performance. API crystals prepared by this method consistently resulted in excellent formulation processing and drug product performance.

Solvent Effects on Catechol Crystal Habits and Aspect Ratios: A Combination of Experiments and Molecular Dynamics Simulation Study

“…Crystal size and shape have essential effects on downstream processing such as filtration, washing and drying for solution crystallization [1][2][3]. Meanwhile, crystal properties such as flowability and bulk density [4,5] are closely associated with crystal morphology.…”

Influence of Filtration on the Agglomeration Degree of Two Crystalline Amino Acids

“…This method is also used in the production of therapeutically proteins because of the resulting reduction of complex chromatography steps [1,2]. Due to the high amount of impurities the final molecule can be obtained in a solid, pure and stable form under great effort.…”

“…The aim of this process is a product with well-defined properties concerning particle size, size distribution, flow and surface characteristics [2,3]. The aim of this process is a product with well-defined properties concerning particle size, size distribution, flow and surface characteristics [2,3].…”

“…Furthermore, agglomeration increases the particle size, so that flowability of the powder is improved and undesired events as tablet capping in the solid dosage form can be reduced [11]. This effect can be improved by agglomeration [2,12]. This effect can be improved by agglomeration [2,12].…”

Engineering Reaction and Crystallization and the Impact on Filtration, Drying, and Dissolution Behaviors: The Study of Acetaminophen (Paracetamol) by In-Process Controls

“…32,33 However, making stable and reproducible pharmaceutical products required monitoring and controlling of the desired PSD from crystallization all the way through various agitated dryers. 34,35 The collective behaviors manifested by different PSDs in blending, wet granulation, and dissolution have also been investigated separately. 36 Therefore, on this objective, we wanted to demonstrate a seamless overall view of manufacturing bioactive drug substances or active pharmaceutical ingredients (APIs) from chemical synthesis to solution crystallization where crystal engineering can influence PSD and downstream operations.…”