The impact of direct nucleation control on crystal size distribution in pharmaceutical crystallization processes

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events is necessary to achieve the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the apparent onset of nucleation defined as the formation of new particles with detectable size using in situ instruments. The approach uses information on nucleation and dissolution, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating protocol, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve. The DNC approach automatically and adaptively detects the boundary of the operating zone; hence it is more robust to the presence of impurities or residual solvent than the supersaturation control approach. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations

Monitoring continuous crystallization of paracetamol in the presence of an additive using an integrated PAT array and multivariate methods

In this study, an automated intelligent decision support (IDS) framework was applied to monitor the continuous crystallization of form I paracetamol (PCM) and determine steady-state operation. A modified single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to investigate methods to minimize early onset of fouling and encrustation by carrying out crystallizations in the presence and absence of hydroxyl propyl methyl cellulose (HPMC) additive. The effectiveness of HPMC toward controlling the crystallization process and alleviating fouling and encrustation for prolonged operation of the MSMPR was investigated over a range of concentrations. HPMC was found to suppress nucleation and growth, thereby controlling the crystallization and alleviating fouling and encrustation over extended operating periods. HPMC also affected the product crystal morphology, leading to predominantly tabular shaped crystals. Steady state in the MSMPR was characterized using the IDS, which consisted of an integrated and ancillary array of process analytical technologies (PAT), including the application of Raman spectroscopy with multivariate calibration for solution phase concentration measurement

Direct nucleation control of crystal size distribution in pharmaceutical crystallization

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events will result in the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the onset of nucleation. The approach uses information on nucleation, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating policy, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve; the system automatically and adaptively detects the boundary of the operating curve. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations

The impact of direct nucleation control on crystal size distribution in pharmaceutical crystallization processes

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events is necessary to achieve the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the apparent onset of nucleation defined as the formation of new particles with detectable size using in situ instruments. The approach uses information on nucleation and dissolution, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating protocol, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve. The DNC approach automatically and adaptively detects the boundary of the operating zone; hence it is more robust to the presence of impurities or residual solvent than the supersaturation control approach. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations

Toward Continuous Crystallization of Urea-Barbituric Acid: A Polymorphic Co-Crystal System

Pharmaceutical co-crystals are multicomponent molecular systems typically formed through hydrogen bonding of a co-former molecule with the active pharmaceutical ingredient (API). Just as many single component molecular structures can exhibit polymorphism due to the geometry of hydrogen bond donors and acceptors, the same is true for pharmaceutical co-crystals. In this study, the selective co-crystallization of the desired polymorphic form of urea-barbituric acid (UBA) co-crystals (forms I and III) is demonstrated, applying a novel periodic mixed suspension mixed product removal (PMSMPR) crystallizer cascade. The process was monitored using an integrated process analytical technology (PAT) array consisting of Raman spectroscopy, attenuated total reflectance ultraviolet/visible (ATR-UV/vis) spectroscopy, focused beam reflectance measurement (FBRM), particle vision microscopy (PVM), and an in-house developed commercial crystallization process informatics system (CryPRINS) software tool to determine when a “state of controlled operation” (SCO) was achieved. Three different start-up strategies were employed and their ability to produce selectively a particular polymorphic form of UBA was evaluated. The experimental conditions for producing pure UBA form I were optimized, but pure UBA form III remained elusive. Off-line characterization of the UBA polymorphs was carried out using Powder X-ray Diffraction (PXRD) and Raman spectroscopy

Nomogram predicting the probability of spontaneous stone passage in patients presenting with acute ureteric colic

Objectives To develop a nomogram that could predict spontaneous stone passage (SSP) in patients presenting with acute ureteric colic who are suitable for conservative management. Patients and Methods A 2517 patient dataset was utilised from an international multicentre cohort study (MIMIC, A Multi-centre Cohort Study Evaluating the role of Inflammatory Markers In Patients Presenting with Acute Ureteric Colic) of patients presenting with acute ureteric colic across 71 secondary care hospitals in the UK, Ireland, Australia, and New Zealand. Inclusion criteria mandated a non-contrast computed tomography of the kidneys, ureters, and bladder. SSP was defined as the ‘absence of the need for intervention’. The model was developed using logistic regression and backwards selection (to achieve lowest Akaike's information criterion) in a subset from 2009–2015 (n = 1728) and temporally validated on a subset from 2016–2017 (n = 789). Results Of the 2517 patients, 1874 had SSP (74.5%). The mean (SD) age was 47 (14.7) years and 1892 were male (75.2%). At the end of the modelling process, gender: male (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.64–1.01, P = 0.07), neutrophil count (OR 1.03, 95% CI 1.00–1.06, P = 0.08), hydronephrosis (OR 0.79, 95% CI 0.59–1.05, P = 0.1), hydroureter (OR 1.3, 95% CI 0.97–1.75, P = 0.08), stone size >5–7 mm (OR 0.2, 95% CI 0.16–0.25, P 7 mm (OR 0.11, 95% CI 0.08–0.15, P < 0.001), middle ureter stone position (OR 0.59, 95% CI 0.43–0.81, P = 0.001), upper ureter stone position (OR 0.31, 95% CI 0.25–0.39, P < 0.001), medical expulsive therapy use (OR 1.36, 95% CI 1.1–1.67, P = 0.001), oral nonsteroidal anti-inflammatory drug (NSAID) use (OR 1.3, 95% CI 0.99–1.71, P = 0.06), and rectal NSAID use (OR 1.17, 95% CI 0.9–1.53, P = 0.24) remained. The concordance-statistic (C-statistic) was 0.77 (95% CI 0.75–0.80) and a nomogram was developed based on these. Conclusion The presented nomogram is available to use as an on-line calculator via www.BURSTurology.com and could allow clinicians and patients to make a more informed decision on pursuing conservative management vs early intervention