(M1230-08-47) Varied Bulk Powder Properties as a Result of Particle Engineering Methods for Micronized API: Implications of Crystal Surface Anisotropy for Materials within Size Specifications

Purpose: In the past few decades, many particle engineering techniques have been developed to prepare fine particles of pharmaceutical compounds to enhance their dissolution rate and bioavailability.¹ Among them, milling (a “top-down” method) and precipitation (a “bottom-up” method) are the most commonly used techniques. However, both have known limitations that influence the quality of engineered particles. The high energy input of the milling process may result in phase change, such as amorphization and polymorphic transition, broad particle size distribution, metal shedding, and surface anisotropy.^2–4 On the other hand, insufficient mixing and extensive aggregation of small particles could also lead to broad particle size distribution during liquid anti-solvent crystallization.⁵ Moreover, the crystal shape obtained by anti-solvent crystallization is sensitive to crystallization parameters employed.⁶ While diverse particle engineering routes offer several options to achieve target size specifications, the full impact of different engineering routes on bulk powder properties can be more complex. Due to different morphologies and surface energetics of crystals, arising from the anisotropy of molecular crystals, fine drug powders can still behave quite differently in downstream processing due to their different bulk powder properties. This work systematically characterizes key bulk powder properties of 8 batches of fine crystals of a model active pharmaceutical ingredient (API) obtained through both jet-milling and fast precipitation.

Methods: Odancatib was selected as a model drug. Six batches of Odanacatib were prepared by jet milling methods. Two were obtained from manufacturing-scale milling of unique API lots. The other four batches were prepared with lab-scale jet milling, using crystalline API with differentiated starting morphologies. The lower aspect ratio solids were jet milled as API-only and with hydrophilic and hydrophobic lubricants, to minimize formation of amorphous content. The higher aspect ratio morphology was milled as API-only. Two additional batches were obtained by fast precipitation from different solvents (Figure 1). Particle size distributions were obtained by laser diffraction. X-ray Diffractometry was used to verify the phase purity and crystallinity of the API batches. Tabletability was studied by preparing a series of compacts obtained over the compaction pressures up to 350 MPa using a compaction simulator. Powder flowability was measured by a shear cell tester (n= 3). Dissolution behavior was studied using an intrinsic dissolution rate (IDR) apparatus (n= 3). Wettability was compared by measuring the contact angles of the tablet of each sample (n= 3). Five representative samples were selected to be made into formulations consisting of 1% API, 27% Avicel PH102, 66% spray-dried lactose, 5% crospovidone, and 1% magnesium stearate. Content uniformity was studied by following USP < 905 > (n= 10).

Results: The particle size specification, d₅₀ < 5 µm, was previously established based on the clinical biopharmaceutical performance of this drug. All 8 powders prepared meet the particle size specification (Table 1). Based on the XRD data, all samples are the same solid form of the API. However, the crystallinity of all samples decreased after compression. Also, jet milling induced the formation of amorphous content in one batch (Figure 2a). The tabletability of all samples is significantly different, where only samples A and P2 could be made into intact tablets (Figure 2b). All API samples are very cohesive, while their flowability differed. With a larger particle size, the unmilled sample A exhibited a better flowability than all corresponding milled samples (Figure 2c). The IDRs among different samples are significantly different. Sample P2, prepared by precipitation from a water and acetone solvent system, shows a considerably higher IDR than other API batches. In addition, IDR was affected by the type of starting material, use of processing aids, and crystallinity (Figure 2d). Similarly, the contact angles are significantly different among all samples studied (Figure 2e). The different bulk properties of samples caused by different preparation routes, may be attributed to the different surface energies. This led to different tablet content uniformity among 5 API lots prepared using a common formulation, with sample A exhibiting the best content uniformity. Content uniformity of formulations containing jet milled API, A1 and B1, is poorer than that by precipitation, P1 and P2 (Figure 2f). This is attributed to the higher surface energy of the jet milled API lots than precipitated ones, which leads to a higher agglomeration tendency.

Conclusion: Different engineering routes could be used to produce API lots that meet the target particle size specifications. However, the processing route does have a measurable impact on the properties of the drug, ranging from powder properties, to solid-state properties, to dissolution, and to content uniformity. Hence, beyond API size specifications, the particle engineering route should be selected considering properties influencing robust manufacturability and drug product performance. In this work, the direct precipitated sample P2 exhibited overall better performance (tabletability, dissolution, and content uniformity) than other processed samples.

References: (1) Kumar, R.; Thakur, A. K.; Chaudhari, P.; Banerjee, N. Particle Size Reduction Techniques of Pharmaceutical Compounds for the Enhancement of Their Dissolution Rate and Bioavailability. J. Pharm. Innov. 2021. https://doi.org/10.1007/s12247-020-09530-5.
(2) Chikhalia, V.; Forbes, R. T.; Storey, R. A.; Ticehurst, M. The Effect of Crystal Morphology and Mill Type on Milling Induced Crystal Disorder. Eur. J. Pharm. Sci. 2006, 27 (1), 19–26. https://doi.org/10.1016/j.ejps.2005.08.013.
(3) Lin, S.-Y.; Hsu, C.-H.; Ke, W.-T. Solid-State Transformation of Different Gabapentin Polymorphs upon Milling and Co-Milling. Int. J. Pharm. 2010, 396 (1), 83–90. https://doi.org/10.1016/j.ijpharm.2010.06.014.
(4) Modi, S. R.; Dantuluri, A. K. R.; Perumalla, S. R.; Sun, C. C.; Bansal, A. K. Effect of Crystal Habit on Intrinsic Dissolution Behavior of Celecoxib Due to Differential Wettability. Cryst. Growth Des. 2014, 14 (10), 5283–5292. https://doi.org/10.1021/cg501084a.
(5) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. H. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol. Rev. 2013, 65 (1), 315–499. https://doi.org/10.1124/pr.112.005660.
(6) ter Horst, J. H.; Geertman, R. M.; van Rosmalen, G. M. The Effect of Solvent on Crystal Morphology. J. Cryst. Growth 2001, 230 (1), 277–284. https://doi.org/10.1016/S0022-0248(01)01341-0.


Figure 1. Preparation routes of all samples studied in this work. Samples A and B with different morphologies are starting materials for jet-milled samples.


Figure 2. Solid-state characterization, bulk properties, and downstream processibility of samples. a. powder and tablet XRD; b. tabletability; c. flowability; d. intrinsic dissolution rate; e. contact angle; f. content uniformity.


Table 1. Particle size distribution of samples