Mechanically induced amorphization of small molecule organic crystals

Abstract

Milling and micronization are commonly used to reduce the particle size of active pharmaceutical ingredients and excipients. During these processes the materials are subjected to extensive deformation that may result in defect nucleation, polymorphic transformations, and amorphization. Current amorphization models require parameters that demand extensive number of experiments. We present a multiscale framework to predict mechanically induced amorphization without experimental information. The model requires as input only the molecular structure and starts with molecular dynamics simulations to determine elastic constants, melting temperature, crystal-amorphous interface energy, and the energy density difference between the amorphous and crystalline phases. This information is used in a phase field model that includes defect nucleation and solid state amorphization. At each scale, the components of the model are validated by performing simulations of sucrose, lactose, acetaminophen, and gamma-indomethacin. The multiscale framework is exercised to predict the response of two pharmaceutical compounds F1 and F2, without any experimental information. The model indicates that F1 is resistant to disorder while F2 tends to be amorphized, in agreement with the experimental results.

Recent Advances in Co-processed APIs and Proposals for Enabling Commercialization of These Transformative Technologies

“…Additive-mediated crystallizations have additional benefits when combined with precipitation based processes to generate micronized materials (<10 μm, generally <5 μm). Conventional routes to access this particle size range typically require dry milling operations, which often generate disordered crystals or amorphous material − that can result in physical or chemical instabilities, or undesirable intrinsic dissolution or flow properties. , Potent compounds also present commercial processing hurdles, as containment during dry milling operations is a concern. The concept of continuous precipitation has received a great deal of interest , including excellent summaries of the fundamentals of the phenomena involved .…”

Preparation and Characterization of Solid Dispersions Composed of Curcumin, Hydroxypropyl Cellulose and/or Sodium Dodecyl Sulfate by Grinding with Vibrational Ball Milling

“…The temperature was controlled at 37 ± 0.5 • C and the rotating paddle speed was set at 100 rpm throughout this study. At defined time intervals (1,3,5,10,15,30,45,60, 90 and 120 min), 5 mL aliquots were withdrawn, and an equal volume of fresh DW was added. The sample solutions were filtered through a 0.45-µm membrane filter and assayed for CUR content using UV-visible spectroscopy at 432 nm as described in the section "Quantification of CUR".…”

“…It is estimated that approximately 70% of the current new drug candidates have poor solubility [1]. One methodology that can enhance the solubility of poorly water-soluble drugs and their bioavailability is amorphization [2][3][4][5]. Indeed, the solubility of amorphous drugs can be up to a 1000-fold higher than that of their crystalline forms [6][7][8][9].…”

“…Amorphous substances can be classified into two categories: molecularly pure drugs and solid dispersions (SDs), where the active pharmaceutical ingredient (API) is dispersed within a carrier(s). Vo et al have demonstrated that SDs can be categorized into four distinct subcategories [10]: (1) SDs that use a crystalline carrier, such as urea [11][12][13] or sugar [11]; (2) SDs that use a polymeric carrier, such as povidone [14], polyethylene glycol [15], hydroxypropyl cellulose [16] or cyclodextrin [17][18][19][20][21]; (3) SDs that use a carrier with surface activity, such as surfactant(s) or a mixture of polymers and surfactants [22]; and (4) controlled release SDs or SDs that use swellable/water insoluble polymers, such as Eudragit ® [23] and Carbopol ® [23].…”