Impact of carrier particle surface properties on drug nanoparticle attachment.

HYPOTHESIS: The stabilization and isolation to dryness of drug nanoparticles has always been a challenge for nano-medicine production. In the past, the use of montmorillonite (MMT) clay carrier particles to adsorb drug nanoparticles and maintain their high surface area to volume ratio after isolation to dryness has proven to be effective. We hypothesise that the distribution of hydrophilic and hydrophobic patches on the clay's surface as well as its porosity/roughness, hinder the agglomeration of the drug nanoparticles to the extent that they retain their high surface area to volume ratio and display fast dissolution profiles. EXPERIMENTS: In this work, the distribution of hydrophobicity and hydrophilicity, and the porosity/roughness, of the surface of selected silica carrier particles were varied and the impact of these variations on drug nanoparticle attachment to the carrier particle and subsequent dissolution profiles was studied. FINDINGS: The fastest dissolution profiles at the highest drug nanoparticle loadings were obtained with a periodic mesoporous organosilane carrier particle which had a homogeneous distribution of hydrophobic and hydrophilic surface properties. Carrier particles with rough/porous surfaces and a combination of hydrophobic and hydrophilic patches resulted in nanocomposite powders with faster dissolution behaviour than carrier particles with predominantly either a hydrophobic or hydrophilic surface, or with non-porous/smoother surfaces.

Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation.

Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomethacin while achieving the desired particle size distribution is described. It was proven that when a metastable form of indomethacin was initially nucleated, the rate of its transformation to the stable form was influenced by the presence of excipients and seeds (17.10 ± 0.20 µm), decreasing from 48 to 4 h. The final particle size (D50) of the indomethacin suspension produced without seeding was 7.33 ± 0.38 µm, and with seeding, it was 5.61 ± 0.14 µm. Additionally, it was shown that the particle size distribution of the seeds and the time point of seed addition were critical to obtain the desired solid-state form and that excipients played a crucial role during nucleation and polymorphic transformation. This alternative, energy-efficient bottom-up method for the production of drug suspensions with a reduced risk of contamination from milling equipment and fewer processing steps may prove to be comparable in terms of stability and particle size distribution to current industrially accepted top-down approaches.

Studying the impact of the pre-exponential factor on templated nucleation.

Traditionally, the enhancement of nucleation rates in the presence of heterogeneous surfaces in crystallisation processes has been attributed to the modification of the interfacial energy of the system according to the classical nucleation theory. However, recent developments have shown that heterogeneous surfaces instead alter the pre-exponential factor of nucleation. In this work, the nucleation kinetics of glycine and diglycine in aqueous solutions have been explored in the presence and absence of a heterogeneous surface. Results from induction time experiments show that the presence of a heterogeneous surface increases the pre-exponential factor by 2-fold or more for both glycine and diglycine, while the interfacial energy remains unchanged for both species. This study suggests that the heterogeneous surface enhances the nucleation rate via hydrogen bond formation with both glycine and diglycine. This is verified by hydrogen bond propensity calculations, molecular functionality analysis, and calculation of the time taken for a solute molecule to attach to the growing nucleus, which is an order of magnitude shorter than the estimated lifetime of the hydrogen bond. The effect of the heterosurface is of greater magnitude for diglycine than for glycine, which may be due to the heightened molecular complementarity between the hydrogen bond donor and acceptor sites on diglycine and the heterosurface.

Preparation, stabilisation, isolation and tableting of valsartan nanoparticles using a semi-continuous carrier particle mediated process.

This work investigated the technical feasibility of preparing, stabilizing and isolating poorly water-soluble drug nanoparticles via a small-scale antisolvent precipitation process operating in semi-continuous mode. Specifically, a novel semi-continuous process was demonstrated for the carrier particle mediated production, stabilization and isolation of valsartan nanoparticles into a solid form using montmorillonite clay particles as the carrier. The semi-continuous process operated robustly for the full duration of the experiment (~16 min) and steady-state conditions were reached after ~5 min. Nanoparticles of valsartan (51 ± 1 nm) were successfully prepared, stabilized and isolated with the help of montmorillonite (MMT) or protamine functionalized montmorillonite (PA-MMT) into the dried form by this semi-continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding laboratory scale batch mode process, indicating that the product quality (principally the nanoscale particle size and solid-state form) is retained during the semi-continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered nanocomposite material. PXRD, DSC, SSNMR and dissolution studies indicate that the valsartan nanoparticles produced via this semi-continuous process were amorphous and exhibited shelf-life stability equivalent to > 10 months.

Extended Lifetime of Molecules Adsorbed onto Excipients Drives Nucleation in Heterogeneous Crystallization.

Monte Carlo (MC) and molecular dynamics (MD) computer simulations were used to investigate the role of adsorption during seeded and heterogeneous crystallization. The simulations characterized the range of adsorption energies and configurations encountered during adsorption of individual molecules of active pharmaceutical ingredients (APIs), with varying hydrogen-bonding tendencies, onto seed and heterosurfaces. Specifically, the adsorption of acetaminophen (AAP), carbamazepine (CBMZ), fenofibrate (FF), phenylbutazone (PBZ), clozapine (CPB), and risperidone (RIS) was simulated on selected crystallographic facets of their own crystals as examples of seeded crystallizations and on lactose or microcrystalline cellulose (MCC) substrates as heterosurfaces. The MC screening provided adsorption enthalpies in the range of -59 to -155 kJ mol-1 for these APIs on lactose, generally increasing as the molar mass of the API increased. The corresponding values predicted for adsorption of each API onto its own crystal were in the range of -92 to -201 kJ mol-1. More detailed MD simulations performed in methanol showed adsorption free energies for RIS on MCC in the range of -37 to -50 kJ mol-1 with strong molecule-surface complexation lifetime of tens of nanoseconds on the (010) face of MCC. This extended lifetime is a key feature in understanding the mechanism of heterogeneous crystallization. A well-formed nucleus is generated on the surface starting with a single adsorbed molecule. Individual or small clusters add to the adsorbed species. This addition is facilitated by the extended lifetime of the adsorbed molecule, which is several orders of magnitude greater than the time required for additional molecules to assemble and grow into a stable nucleus attached to the heterosurface.

Modification of the zeta potential of montmorillonite to achieve high active pharmaceutical ingredient nanoparticle loading and stabilization with optimum dissolution properties.

Nanoparticles (NPs) of three poorly water-soluble BCS class II active pharmaceutical ingredients (APIs) (clozapine (CLO), curcumin (CUR) and carbamazepine (CBMZ) with zeta potentials -28.5 ±â€¯2.5, -33 ±â€¯1.5 and -13 ±â€¯1.5 mV respectively) were produced, stabilized and isolated into the solid state with the help of Montmorillonite (MMT) clay carrier particles. The nanoparticles of clozapine (27 nm), curcumin (170 nm) and carbamazepine (30 nm) were produced and stabilized in suspension using a reverse antisolvent precipitation technique in the presence of 'as received' MMT carrier particles (∼30 µm) and/or MMT carrier particles whose surface had been slightly modified with a cationic protein, protamine sulphate salt (PA). The resulting nanoparticle carrier composites were isolated directly from suspension into a solid state form by simple filtration followed by air-drying. The API dissolution rates from these dried NP-carrier composites were comparable with those of the respective stabilized API nanoparticles in suspension up to maximum CLO, CUR and CBMZ loadings of 23%, 21.8% and 33.3% (w/w) respectively, although surface modification of the MMT carrier particles with PA was needed for the CLO and CUR NP-carrier composites in order to preserve the fast API nanosuspension-like dissolution rates at higher API loadings. For both of these APIs, the optimal loading of PA on MMT was around 4 mg/g, which likely helped to limit aggregation of the API nanoparticles at the higher API loadings. Interestingly, no MMT surface modification was needed to preserve fast API dissolution rates at higher API loadings in the case of the CBMZ NP-carrier composites. This discrimination among the three APIs for carrier particle surface modification was previously observed in reported studies by our group for three other APIs, namely valsartan, fenofibrate and dalcetrapib. When examined together, the data for all six APIs suggest a general trend whereby API nanoparticles with zeta potentials more positive than around -25 mV do not require carrier particle surface modification with PA in order to preserve their fast dissolution rates from NP-carrier composites at higher API loadings. Thus, this study offers a potentially effective means of transforming poorly water soluble BCS Class II APIs into fast dissolving solid dosage NP-carrier composites, whereby the surface properties of the carrier particle can be tuned with prior knowledge of the zeta potential of the API nanoparticles.

Carrier particle mediated stabilization and isolation of valsartan nanoparticles.

Drug nanoparticles are a promising solution to the challenging issues of low dissolution rates and erratic bioavailability due to their greater surface/volume ratio. The central purpose of this study is to prepare, stabilize and isolate nanoparticles of poorly water-soluble active pharmaceutical ingredients (APIs) into a dried form with the help of clay carrier particles. Isolation of nanoparticles from suspension into the dried state is crucial to avoid the problems of aggregation and Ostwald ripening. In this study nanoparticles of the API valsartan were generated via a reverse antisolvent process at high supersaturations. Montmorillonite (MMT) and protamine functionalized montmorillonite (PA-MMT) were employed for stabilization and isolation of the valsartan (Val) nanoparticles (ca. 50 nm) into a dried form. A high dissolution rate of the resultant solid formulation at high drug loadings (up to 33.3% w/w) was achieved. The dissolution rates of the isolated valsartan nanoparticle carrier composites (dried Val-MMT nanocomposites and dried Val-PA-MMT nanocomposites) were similar to that of freshly prepared suspended valsartan nanoparticles, confirming that the high surface area of the nanoparticles is retained during the adsorption and drying processes. Differential scanning calorimetry and PXRD studies indicated that the valsartan nanoparticles were amorphous when adsorbed onto the carrier particles. The dissolution rates of the Val-MMT and Val-PA-MMT nanocomposites were maintained after 10 months' storage which indicates that no aggregation or solid state transformation of the carrier-stabilized Val nanoparticles had occurred.

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20-21, 2014 Continuous Manufacturing Symposium.

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are.

Achieving continuous manufacturing: technologies and approaches for synthesis, workup, and isolation of drug substance. May 20-21, 2014 Continuous Manufacturing Symposium.

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chemistry toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment especially for workup to assist in straightforward deployment in the laboratory. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process analytical technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystallization. Involve all parts of the organization from discovery, research and development, and manufacturing in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chemistry, physical chemistry, and chemical engineering skills at the chemistry-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the critical economic drivers is critical to driving the transformation in manufacturing.

A comparative study of the use of powder X-ray diffraction, Raman and near infrared spectroscopy for quantification of binary polymorphic mixtures of piracetam.

Diffraction and spectroscopic methods were evaluated for quantitative analysis of binary powder mixtures of FII(6.403) and FIII(6.525) piracetam. The two polymorphs of piracetam could be distinguished using powder X-ray diffraction (PXRD), Raman and near-infrared (NIR) spectroscopy. The results demonstrated that Raman and NIR spectroscopy are most suitable for quantitative analysis of this polymorphic mixture. When the spectra are treated with the combination of multiplicative scatter correction (MSC) and second derivative data pretreatments, the partial least squared (PLS) regression model gave a root mean square error of calibration (RMSEC) of 0.94 and 0.99%, respectively. FIII(6.525) demonstrated some preferred orientation in PXRD analysis, making PXRD the least preferred method of quantification.