Experimental Study on the Influence of Excipients on the Heterogeneous Crystallization and Dissolution Properties of an Active Pharmaceutical Ingredient

Abstract

This study is based on the heterogeneous nucleation of active pharmaceutical ingredients (APIs) 2 in the presence of various excipients widely used in the pharmaceutical industry. Carbamazepine (CBMZ) was successfully crystallized in the presence of the following heterosurfaces: α/β-4 Lactose, β-D-Mannitol, microcrystalline cellulose and carboxymethyl cellulose. The successful 5 crystallization of CBMZ FIII in the presence of all the excipients was confirmed by powder X-6 ray diffraction and scanning electron microscopy, while CBMZ crystals apposition was 7 confirmed using in-situ SEM-Raman. A pronounced improvement in the dissolution of CBMZ 8 FIII was observed when crystallized in the presence of excipients when compared with CBMZ 9 FIII recrystallized using same conditions in the absence of the excipients. The isolated solids 10 could be simply tabletted by direction compression upon mixing with the desired amount of 11 disintegrant and lubricant. Hence employing this process could potentially streamline the 12 downstream process in pharmaceutical industries and also increase the throughput with reduced 13 cost. 14

The heterogeneous crystallization of a novel solvate of clozapine base in the presence of excipients

“…These reductions in the induction time of CPB in the presence of excipients are significantly larger than those observed during the crystallisation of carbamazepine (CBMZ) or paracetamol (AAP) in the presence of MCC, previously reported. 18,41 In the case of CPB, as confirmed by PXRD ( Fig. 10), CPB-MeOH solvate crystallised in the presence of each of the three excipients; and as supported by single crystal data (Fig.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…Visual examination of number of vials/vessels crystallized (with time) using microscope or webcam is a common practice for determination of the nucleation kinetics (Arribas Bueno et al, ; Curcio et al, ; Diao et al, ; Hsu et al, ; Tan et al, ). Nucleation kinetics has also been determined by in‐line measurement of solution concentration using Fourier‐transform infrared spectroscopy (Verma et al, ) and turbidimetry (Chadwick et al, ; Quon et al, ). Moreover, simultaneous analysis of both physical form and concentration can be undertaken using near‐infrared spectroscopic probe as a process analyzer (Schaefer et al, ).…”

“…Verma et al demonstrated that carbamazepine crystallizes as a stable crystalline form III in the presence of microcrystalline cellulose and carboxymethyl cellulose, where the heteronucleants have improved the process efficiency with simultaneous improvement in dissolution performance of carbamazepine. The process was also scaled‐up to 600 ml from 20 ml with consistent particulate attributes of carbamazepine (Verma et al, ). Yazdanpanah et al demonstrated heterogeneous crystallization of PCM in presence of lactose monohydrate at scale of 5,000 ml.…”

“…Controlling particle size by incorporation of excipients that preferentially binds to the growing face of the API has been known from decades (Shekunov & York, 2000). However, recent reports have shown the use of solid surfaces which not only improves process efficiency but also helps in controlling the particle size of the API (Arribas Bueno et al, 2018;Verma et al, 2017;Yang & Myerson, 2015) (Figure 4). Metastable polymorphic form II of mefenamic acid was crystallized on SAM with particle size as small as $300 nm (Yang et al, 2012).…”

“…Process analysers have been designed to evaluate the critical material attributes of API. Process analysers implemented in the reported literature of heteronuclear crystallization include UV-vis spectrophotometry (Patel et al, 2016), turbidimetry (Quon et al, 2013), Fourier transform infrared spectroscopy (Yazdanpanah et al, 2017), and visual examination (Verma et al, 2017). Majority of reported studies used off-line analysis of polymorphic outcome using powder x-ray diffractometer (Lee et al, 2010;Tipduangta et al, 2015;Zencirci et al, 2009), Raman spectroscopy (Mitchell et al, 2001;Price et al, 2005;Roy et al, 2016;Warzecha et al, 2017) and Fouriertransform infrared spectroscopy (Patel et al, 2016;Zencirci et al, 2009).…”