Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

Abstract

Pulmonary inhalation is increasingly being selected as a preferred route for the delivery of both small and large drug macromolecules for the treatment of a range of pathologies. The direct crystallization of micronized powders, in particular, paracetamol, remains difficult, as it requires the ability to work in high solution supersaturations where agglomeration, wall crusting, and heterogeneous nucleation hinder the control of crystal size and crystal size distribution. Polymer additives are recognized to help drive the production of a given polymorph or controlling crystal shape by means of adsorption on the crystal surface. With the aim of exploiting the polymer-control nucleation and growth of crystals for enhanced direct crystallization of micronized powders, batch cooling crystallization of paracetamol in water was carried out in the presence of 0.1−0.8% w/w hydroxypropyl methylcellulose (HPMC). In the presence of polymer, the onset of nucleation was delayed and extended beyond the cooling time of the solution, resulting in an isothermal cooling crystallization and the production of micronized paracetamol with a mean crystal size D 50 , in the range of 15−20 μm and an improved crystal size distribution. Equally, the rate generation of solution cloudiness was reduced by over 3-fold for the highest HPMC concentration tested, with no detectable impact on final product yield. The mechanisms for nucleation delay and growth inhibition by HPMC is unknown; however, a modification of crystal's shape observed upon the addition of HPMC to the solution suggested it might be related to mass transfer limitations and intermolecular hydrogen bonding between the large HPMC and the small drug molecules. This technique can potentially be used for direct crystallization of other micronized drugs.

Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays

“…It can be explained by HPMC molecules forming hydrogen bonds with water, which can immobilize water molecules and hinder their incorporation into the crystal lattice. 26 , 56 , 57 Similar behavior was observed by Tian et al, 58 who found that the phase transformation of anhydrous carbamazepine polymorphic forms I and III to the dihydrate was inhibited in aqueous HPMC solutions. In addition, HPMC can form hydrogen bonds with PRX via OH groups in HPMC and PRX molecules.…”

“… 13 − 17 It has been used to prepare ultrafine powders and micro-/nanodispersions of many APIs, including budesonide, 18 danazol, 19 beclomethasone dipropionate, 20 griseofulvin and fenofibrate, 21 salbutamol sulfate, 22 prednisolone, 23 atorvastatin, 24 l -glutamic acid, 25 and paracetamol. 26 …”

Tuning Crystal Morphology of Succinic Acid Using a Polymer Additive

“…[7][8][9] Borsos et al have recently developed a control strategy to tailor the shape of crystals of potassium dihydrogen phosphate using two different growth modifiers, aluminum sulphate and sodium hexametaphosphate. 10,11 In some cases impurities are deliberately added to a crystallization to engineer the growth of crystals with a desired morphology (by inhibiting growth of selected faces); these are known as additives and they can be used to control the shape of the final crystals, [12][13][14][15][16] their size [17][18][19][20] and polymorphic form. 21,22 There is a broad array of examples of the effect of structurally similar additives on crystal morphology, [23][24][25][26][27][28][29][30][31][32] including the well-known examples of urea crystallized in the presence of biuret 33 and benzamide with benzoic acid.…”

Influence of Cationic Surfactants on the Crystallization of Cis‐ and Trans‐Isomers

“…In solution crystallization, many studies have shown that the presence of impurities often has a great influence on the nucleation and growth of crystals, leading to changes in the polymorphic form or shape (Majumder & Nagy, ; Poornachary, Chow, & Tan, , ; Reis, Liu, Reis, & Mackley, ; Şahin, Özdemir, & Genli, ; Saleemi, Onyemelukwe, & Nagy, ; Yang, Song, Ying, Chen, & Heng, ). In fact, impurities such as dust are inevitable in an actual crystallization system.…”