Investigation of the Evolution of Crystal Size and Shape during Temperature Cycling and in the Presence of a Polymeric Additive Using Combined Process Analytical Technologies

Abstract

Crystal size and shape can be manipulated to enhance the qualities of the final product. In this work the steady-state shape and size of succinic acid crystals, with and without a polymeric additive (Pluronic P123) at 350 mL, scale is reported. The effect of the amplitude of cycles as well as the heating/cooling rates is described, and convergent cycling (direct nucleation control) is compared to static cycling. The results show that the shape of succinic acid crystals changes from plate- to diamond-like after multiple cycling steps, and that the time required for this morphology change to occur is strongly related to the type of cycling. Addition of the polymer is shown to affect both the final shape of the crystals and the time needed to reach size and shape steady-state conditions. It is shown how this phenomenon can be used to improve the design of the crystallization step in order to achieve more efficient downstream operations and, in general, to help optimize the whole manufacturing process.

Tuning Morphology in Active Pharmaceutical Ingredients: Controlling the Crystal Habit of Lovastatin through Solvent Choice and Non-Size-Matched Polymer Additives

“…45 Choice of Additives. Non-size-matched additives were chosen by reference to literature studies, where API crystal habit and growth conditions have been successfully controlled using large polymer additives, 14,15 and from a small available library of polymer additives. Building on the results of crystal face indexing studies, polymers with both hydrophilic (PEG-200) and hydrophobic (PPG-4000) properties were selected to allow further investigation of how hydrophilic/phobic components can affect the lovastatin needle thickness.…”

“…Temperature cycling experiments were first carried out in pure ethyl acetate solution; such methods have previously been shown to influence API crystal shape. 15 To investigate this, the effect of moving to a nonevaporative crystallization method on the lovastatin crystal morphology must first be assessed. Using a combination of literature solubility 50 and experimental solubility data (Figure 6) as a guideline, test experiments were first carried out at concentration levels of 4.6%, 3.2%, 2.2%, and 1.6% m/m to allow the optimum conditions to be selected.…”

“…22,26,27 Examples of soluble additives in the literature include: simple inorganic ions (e.g. Li + or K + ), 28 low mass organic additives, 20,26,29,30 surfactants, 23,31,32 polymer additives (including homopolymers 22,30,33 and block co-polymers 14,15,34 ), and bio-/macromolecules. 21 For the crystallization of APIs, where the choice of additive must be restricted to compatible materials e.g.…”

Time-Resolved X-ray Phase-Contrast Imaging (XPCI) of Nucleation and Crystal Growth in the Anti-Solvent Crystallization of Lovastatin

“…Lovastatin is widely known to exhibit a needle-like habit 49 that causes problems with processing and manufacturing of API [49][50][51][52][53][54][55][56][57][58] during filtering 58 and due to poor flow properties. 59 This morphology is known to arise from solvent interactions leading to slow growth of various facets.…”

Crystal Morphology Modification of 5, 5′‐Bisthiazole‐1,1′‐ dioxyhydroxyammonium Salt

“…Different crystal morphologies directly affect their performance and physical properties as well as processing. Generally, crystals having a smooth surface and an approximately spherical shape have better dispersibility and lower sensitivity than elongated needle‐like crystals or dendritic irregular crystals . For example, Liu et al found the spheroidized 1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocine (HMX) with a higher initial temperature and better thermal stability than the feedstock.…”