Applying real life examples for improved learning outcomes

The aim of this project was to redesign and optimize a classroom lesson within the course “Drug Formulation” for BSc students in pharmacy by applying a ‘problem to solve’ teaching style in order to improve the students ability to apply and crosslink their knowledge about pharmaceutical formulations, i.e. support deeper learning and understanding rather than memory

Influence of Solvent Composition on the Performance of Spray-Dried Co-Amorphous Formulations

Ball-milling is usually used to prepare co-amorphous drug–amino acid (AA) mixtures. In this study, co-amorphous drug–AA mixtures were produced using spray-drying, a scalable industrially preferred preparation method. The influence of the solvent type and solvent composition was investigated. Mixtures of indomethacin (IND) and each of the three AAs arginine, histidine, and lysine were ball-milled and spray-dried at a 1:1 molar ratio, respectively. Spray-drying was performed at different solvent ratios in (a) ethanol and water mixtures and (b) acetone and water mixtures. Different ratios of these solvents were chosen to study the effect of solvent mixtures on co-amorphous formulation. Residual crystallinity, thermal properties, salt/partial salt formation, and powder dissolution profiles of the IND–AA mixtures were investigated and compared to pure crystalline and amorphous IND. It was found that using spray-drying as a preparation method, all IND–AA mixtures could be successfully converted into the respective co-amorphous forms, irrespective of the type of solvent used, but depending on the solvent mixture ratios. Both ball-milled and spray-dried co-amorphous samples showed an enhanced dissolution rate and maintained supersaturation compared to the crystalline and amorphous IND itself. The spray-dried samples resulting in co-amorphous samples were stable for at least seven months of storage

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallization of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. In the present study we provide terahertz spectroscopy evidence on the crystallization of amorphous naproxen well below its glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallization. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallization in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

Process Optimization and Upscaling of Spray-Dried Drug-Amino acid Co-Amorphous Formulations

The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 22 full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (Fatom, from 0.5 to 1.4 kg/h) and outlet temperature (Tout, from 55 to 75 °C) were chosen as the critical process parameters. The obtained amorphization, glass transition temperature, bulk density, yield, and particle size distribution were chosen as the critical quality attributes. In general, the model showed low Fatom and high Tout to be beneficial for the desired product characteristics (a co-amorphous formulation with a low bulk density, high yield, and small particle size). In addition, only a low Fatom and high Tout led to the desired complete co-amorphization, while a minor residual crystallinity was observed with the other combinations of Fatom and Tout. Finally, upscaling to a pilot scale spray dryer was carried out based on the DoE results; however, the drying gas flow rate and the feed flow rate were adjusted to account for the different drying chamber geometries. An increased likelihood to achieve complete amorphization, because of the extended drying chamber, and hence an increased residence time of the droplets in the drying gas, was found in the pilot scale, confirming the feasibility of upscaling spray drying as a production technique for co-amorphous systems

The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers

The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer

Glass-Transition Temperature of the β-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs.

Recrystallization of amorphous drugs is currently limiting the simple approach to improve solubility and bioavailability of poorly water-soluble drugs by amorphization of a crystalline form of the drug. In view of this, molecular mobility, α-relaxation and β-relaxation processes with the associated transition temperatures Tgα and Tgβ, was investigated using dynamic mechanical analysis (DMA). The correlation between the transition temperatures and the onset of recrystallization for nine amorphous drugs, stored under dry conditions at a temperature of 296 K, was determined. From the results obtained, Tgα does not correlate with the onset of recrystallization under the experimental storage conditions. However, a clear correlation between Tgβ and the onset of recrystallization was observed. It is shown that at storage temperature below Tgβ, amorphous nifedipine retains its amorphous form. On the basis of the correlation, an empirical correlation is proposed for predicting the onset of recrystallization for drugs stored at 0% RH and 296 K

Development of a multiparticulate drug delivery system for in situ amorphisation

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system

Comparative study of different methods for the prediction of drug-polymer solubility

YesIn this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility.The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.)