Effect of process conditions on particle size and shape in continuous antisolvent crystallisation of lovastatin

Lovastatin crystals often exhibit an undesirable needle-like morphology. Several studies have shown how a needle-like morphology can be modified in antisolvent crystallisation with the use of additives, but there is much less experimental work demonstrating crystal shape modification without the use of additives. In this study, a series of unseeded continuous antisolvent crystallisation experiments were conducted with the process conditions of supersaturation, total flow rate, and ultrasound level being varied to determine their effects on crystal size and shape. This experimental work involved identifying acetone/water as the most suitable solvent/antisolvent system, assessing lovastatin nucleation behaviour by means of induction time measurements, and then designing and implementing the continuous antisolvent crystallisation experiments. It was found that in order to produce the smallest and least needle-like particles, the maximum total flow rate and supersaturation had to be combined with the application of ultrasound. These results should aid development of pharmaceutical manufacturing processes where the ability to control particle size and shape would allow for optimisation of crystal isolation and more efficient downstream processing

Non-invasive monitoring of the growth of metal–organic frameworks (MOFs) via Raman spectroscopy

The applicability of Raman spectroscopy for phase discrimination of metal–organic frameworks (MOFs) has been demonstrated with F4_MIL-140A(Ce) and F4_UiO-66(Ce); analogues prepared from the same metal and ligand sources. Each analogue exhibits unique Raman peaks, with significant differences in the low frequency region, which is more sensitive to structural variations. Non-invasive Raman monitoring of F4_MIL-140A(Ce) synthesis indicated evolution of a unique MOF Raman peak with reaction progress; conversion of this Raman signal to extent of crystallisation was in good agreement with reported reaction kinetics determined via a synchrotron diffraction method. Additionally, Raman spectroscopy indicated initial rapid consumption of the nitric acid modulator present in the reaction coinciding with an expected high probability of nucleation. Raman spectroscopy is a promising technique for rapid screening of MOFs and can be used to study the mechanism of their formation in situ with kinetic insight into both the solution and solid phases of the reaction medium

Crystal structure of a copper-mefenamate complex solvated with diglyme and water

In the copper-mefenamate complex, the asymmetric unit comprises a Cu(II) cation coordinated to two mefenamate ligands solvated with a water molecule and diglyme molecule. The complex adopts a paddlewheel motif and is compared to structural analogues crystallised with dimethylformamide and dimethyl sulfoxide

Surveillance of emerging drugs of abuse in Hong Kong: Validation of an analytical tool

© 2015, Hong Kong Academy of Medicine Press. All rights reserved. Objective: To validate a locally developed chromatography-based method to monitor emerging drugs of abuse whilst performing regular drug testing in abusers. Design: Cross-sectional study. Setting: Eleven regional hospitals, seven social service units, and a tertiary level clinical toxicology laboratory in Hong Kong. Participants: A total of 972 drug abusers and high-risk individuals were recruited from acute, rehabilitation, and high-risk settings between 1 November 2011 and 31 July 2013. A subset of the participants was of South Asian ethnicity. In total, 2000 urine or hair specimens were collected. Main outcome measures: Proof of concept that surveillance of emerging drugs of abuse can be performed whilst conducting routine drug of abuse testing in patients. Results: The method was successfully applied to 2000 samples with three emerging drugs of abuse detected in five samples: PMMA (paramethoxymethamphetamine), TFMPP [1-(3-trifluoromethylphenyl)piperazine], and methcathinone. The method also detected conventional drugs of abuse, with codeine, methadone, heroin, methamphetamine, and ketamine being the most frequently detected drugs. Other findings included the observation that South Asians had significantly higher rates of using opiates such as heroin, methadone, and codeine; and that ketamine and cocaine had significantly higher detection rates in acute subjects compared with the rehabilitation population. Conclusions: This locally developed analytical method is a valid tool for simultaneous surveillance of emerging drugs of abuse and routine drug monitoring of patients at minimal additional cost and effort. Continued, proactive surveillance and early identification of emerging drugs will facilitate prompt clinical, social, and legislative management.Link_to_subscribed_fulltex

Integrated continuous process design for crystallisation, spherical agglomeration, and filtration of lovastatin

Purpose This work seeks to improve the particle processability of needle-like lovastatin crystals and develop a small-footprint continuous MicroFactory for its production. Methods General conditions for optimal spherical agglomeration of lovastatin crystals and subsequent product isolation are developed, first as batch processes, and then transferred to continuous MicroFactory operation. Results Methyl isobutyl ketone is a suitable bridging liquid for the spherical agglomeration of lovastatin. Practical challenges including coupling unit operations and solvent systems; mismatched flow rates and inconsistent suspension solid loading were resolved. The successful continuous production of lovastatin spherical agglomerates (D50 = 336 µm) was achieved. Spherical agglomeration increased the density of the bulk lovastatin powder and improved product flowability from poor to good, whilst maintaining lovastatin tablet performance. Conclusion A continuous, integrated MicroFactory for the crystallisation, spherical agglomeration, and filtration of lovastatin is presented with improved product particle processability. Up to 16,800 doses of lovastatin (60 mg) can be produced per day using a footprint of 23 m2

Digital process design to define and deliver pharmaceutical particle attributes

A digital-first approach to produce quality particles of an active pharmaceutical ingredient across crystallisation, washing and drying is presented, minimising material requirements and experimental burden during development. To demonstrate current predictive modelling capabilities, the production of two particle sizes (D90 = 42 and 120µm) via crystallisation was targeted to deliver a predicted, measurable difference in in vitro dissolution performance. A parameterised population balance model considering primary nucleation, secondary nucleation, and crystal growth was used to select the modes of production for the different particle size batches. Solubility prediction aided solvent selection steps which also considered manufacturability and safety selection criteria. A wet milling model was parameterised and used to successfully produce a 90g product batch with a particle size D90 of 49.3µm, which was then used as the seeds for cooling crystallisation. A rigorous approach to minimising physical phenomena observed experimentally was implemented, and successfully predicted the required conditions to produce material satisfying the particle size design objective of D90 of 120µm in a seeded cooling crystallisation using a 5-stage MSMPR cascade. Product material was isolated using the filtration and washing processes designed, producing 71.2g of agglomerated product with a primary particle D90 of 128µm. Based on experimental observations, the population balance model was reparametrised to increase accuracy by inclusion of an agglomeration terms for the continuous cooling crystallisation. The dissolution performance for the two crystallised products is also demonstrated, and after 45minutes 104.0mg of the D90 of 49.3µm material had dissolved, compared with 90.5mg of the agglomerated material with D90 of 128µm. Overall, 1513g of the model compound was used to develop and demonstrate two laboratory scale manufacturing processes with specific particle size targets. This work highlights the challenges associated with a digital-first approach and limitations in current first-principles models are discussed that include dealing ab initio with encrustation, fouling or factors that affect dissolution other than particle size

A coordination network featuring two distinct copper(II) coordination environments for highly selective acetylene adsorption

Single crystals of 2D coordination network {Cu2L2 ⋅ (DMF)3(H2O)3}n (1-DMF) were prepared by reaction of commercial reagents 3-formyl-4-hydroxybenzoic acid (H2L) and Cu(NO3)2 in dimethylformamide (DMF). The single-crystal structure shows two distinct Cu(II) coordination environments arising from the separate coordination of Cu(II) cations to the carboxylate and salicylaldehydato moieties on the linker, with 1D channels running through the structure. Flexibility is exhibited on solvent exchange with ethanol and tetrahydrofuran, while porosity and the unique overall connectivity of the structure are retained. The activated material exhibits type I gas sorption behaviour and a BET surface area of 950 m2 g−1 (N2, 77 K). Notably, the framework adsorbs negligible quantities of CH4 compared with CO2 and the C2Hn hydrocarbons. It exhibits exceptional selectivity for C2H2/CH4 and C2H2/C2Hn, which has applicability in separation technologies for the isolation of C2H2

Model driven crystallization design and development for mefenamic acid

PREDICTION FIRST API continuous crystallization challenge: building first-principles models, fitting the kinetic parameters to well-designed, minimal set of experiment

Digital design of end-to-end manufacturing process for mefenamic acid using mechanistic modelling

Conference abstract