Amorphous solid dispersions of ketoprofen and poly-vinyl polymers prepared via electrospraying and spray drying: A comparison of particle characteristics and performance.

The purpose of this work was to compare the particle characteristics and dissolution performance of amorphous solid dispersions (ASDs) of ketoprofen and vinyl-pyrrolidone based polymers prepared using electrospraying and spray drying methods. Solution characteristics (surface tension, viscosity and conductivity) were determined for ethanolic solutions containing different vinyl-pyrrolidone based polymers (PVP and PVPVA) and different ketoprofen to polymer mass ratios. The only statistically significant difference in solution properties between PVP and PVPVA systems was electrical conductivity. The higher conductivity in PVP-containing solutions resulted in smaller, more spherical particles than the equivalent formulations prepared with PVPVA when processed via electrospraying. Electrospraying resulted in powders with higher specific surface area, smaller mean particle size, and narrower particle size distribution relative to the spray-dried material. Amorphisation of ketoprofen via both processes was confirmed using pXRD, DSC and FTIR. Although the specific surface area of the electrosprayed powder was higher than the equivalent spray-dried system, this did not translate into a faster dissolution rate at pH 1.2 but did lead to a faster surface moisture adsorption rate at various relative humidities. The flowability of the powder produced via the electrospraying process is poor compared to the equivalent powder produced via spray drying, which may cause challenges in downstream processing. While the ASD powder produced via electrospraying had a smaller particle size and narrower size distribution compared to equivalent spray-dried ASD, further refinement in terms of a final formulation is needed to translate this benefit into an improved dissolution rate in the case of ketoprofen.

In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing.

Different pharmaceutical manufacturing processes have been demonstrated to represent feasible platforms for the production of pharmaceutical cocrystals. However, new methods are needed for the manufacture of cocrystals on a large scale. In this work, the suitability of the use of a fluidized bed system for granulation and concomitant cocrystallization was investigated. Dapsone (DAP) and caffeine (CAF) have been shown to form a stable cocrystal by simple solvent evaporation. DAP is the active pharmaceutical ingredient (API) and CAF is the coformer. In the present study, DAP-CAF cocrystals were produced through liquid-assisted milling and the product obtained was used as a cocrystal reference. The granulation of DAP and CAF was carried out using four different experimental conditions. The solid-state properties of the constituents of the granules were characterised by differential scanning calorimetry (DSC) and x-ray powder diffraction (PXRD) analysis while the granule size distribution and morphology were investigated using laser diffraction and scanning electron microscopy (SEM), respectively. DAP-CAF cocrystal granules were successfully produced during fluidized bed granulation. The formation of cocrystals was possible only when the DAP and CAF were dissolved in the liquid phase and sprayed over the fluidized solid particles. Furthermore, the presence of polymers in solution interferes with the cocrystallization, resulting in the amorphization of the DAP and CAF. Cocrystallization via fluidized bed granulation represents a useful tool and a feasible alternative technique for the large scale manufacture of pharmaceutical cocrystals for solid dosage forms.

Engineering of pharmaceutical cocrystals in an excipient matrix: Spray drying versus hot melt extrusion.

The comparison of spray drying versus hot melt extrusion (HME) in order to formulate amorphous solid dispersions has been widely studied. However, to the best of our knowledge, the use of both techniques to form cocrystals within a carrier excipient has not previously been compared. The combination of ibuprofen (IBU) and isonicotinamide (INA) in a 1:1 M ratio was used as a model cocrystal. A range of pharmaceutical excipients was selected for processing - mannitol, xylitol, Soluplus and PVP K15. The ratio of cocrystal components to excipient was altered to assess the ratios at which cocrystal formation occurs during spray drying and HME. Hansen Solubility Parameter (HSP) and the difference in HSP between the cocrystal and excipient (ΔHSP) was employed as a tool to predict cocrystal formation. During spray drying, when the difference in HSP between the cocrystal and the excipient was large, as in the case of mannitol (ΔHSP of 18.3 MPa0.5), a large amount of excipient (up to 50%) could be incorporated without altering the integrity of the cocrystal, whereas for Soluplus and PVP K15, where the ΔHSP was 2.1 and 1.6 MPa0.5 respectively, the IBU:INA cocrystal alone was only formed at a very low weight ratio of excipient, i.e. cocrystal:excipient 90:10. Remarkably different results were obtained in HME. In the case of Soluplus and PVP K15, a mixture of cocrystal with single components (IBU and INA) was obtained even when only 10% excipient was included. In conclusion, in order to reduce the number of unit operations required to produce a final pharmaceutical product, spray drying showed higher feasibility over HME to produce cocrystals within a carrier excipient.

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating.

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher Cmax), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

Production of cocrystals in an excipient matrix by spray drying.

Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa0.5), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures.

Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties.

The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties.

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals.

Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules.

Drug-polymer miscibility across a spray dryer: a case study of naproxen and miconazole solid dispersions.

The structural and physical stability of solid dispersions have not been adequately explored during spray drying manufacturing processes. In this study a wide range of compositions of naproxen/PVP-VA 64 (poly(1-vinylpyrrolidone-co-vinyl acetate)) and miconazole/PVP-VA 64 solid dispersions prepared by different laboratory spray dryers were collected from various selected locations and used to investigate the drug-polymer mixing across spray dryers. Spray-dried dispersions with 30% (w/w) naproxen collected from the transport tube of the Pro-C-epT Microspray dryer showed the narrowest glass transition width, which apparently indicates the highest degree of drug-polymer mixing compared to the other locations. The intensity of the naproxen-PVP-VA 64 interaction peak at 1654 cm(-1) of IR spectra differs for solid dispersions (SDs) from the collector and transport tube of Pro-C-epT Microspray dryer with a higher intensity for the latter. Samples with 50% (w/w) naproxen loading collected from the cyclone and the cyclone steel part of the Buchi mini spray dryer showed a melting endotherm (Tm at 112.2 ± 0.8 °C and ΔHf between 0.7 and 1.8 J/g), whereas samples from the cyclone tube to the drying chamber were devoid of crystalline material. The variations in drug-polymer mixing extend to miconazole/PVP-VA solid dispersions where 20% drug loading showed location-dependent drug-polymer mixing. This study clearly showed that the variation in drug-polymer miscibility and solid form of the drug in solid dispersions can occur across spray dryer in small-scale manufacturing processes. The optimization of formulation parameters and spray drying process parameters is imperative to diminish these variations to enhance homogeneity of solid dispersions in laboratory scale spray dryers. The same problem can occur in geometrically large spray drying manufacturing equipment, and the robustness of the processes should be carefully assessed.

Influence of compression forces on the structural stability of naproxen/PVP-VA 64 solid dispersions.

Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. The structural stability of the solid dispersions has not been adequately explored during post spray drying manufacturing processes. In this paper, we describe the influence of compression forces on solid dispersions made up of naproxen and PVP-VA 64 prepared by spray drying. Compression of the solid dispersion containing 30% (w/w) of naproxen led to low intensity of the powder X-ray diffraction (PXRD) halo pattern maxima at 2θ = 16.11°, and the uncompressed samples also exhibit higher glass transition broadening than the compressed samples after 21 days storage at 75% RH at ambient temperature which indicates structural changes in the solid dispersion. The intensity of the vibration band at 1654 cm(-1) originating from the interaction between the hydrogen of the carboxylic acid moiety of NAP and the amide carbonyl moiety of PVP-VA 64 was increased for the compressed samples. The consequence of compression was further amplified after a long-term stability study (5 months) where the compressed 40 and 50% (w/w) NAP/PVP-VA 64 solid dispersions showed less crystallinity than the uncompressed samples. This suggests that compression improved the physical stability of the solid dispersions as a result of enhanced drug-polymer interactions.

Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations.

Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics.

Oral formulation strategies to improve solubility of poorly water-soluble drugs.

INTRODUCTION: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. AREAS COVERED: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. EXPERT OPINION: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.