Sai Prasanth Chamarthy

Elucidating Raw Material Variability—Importance of Surface Properties and Functionality in Pharmaceutical Powders

The purpose of this study is to illustrate, with a controlled example, the influence of raw material variability on the excipient’s functionality during processing. Soluble starch was used as model raw material to investigate the effect of variability on its compaction properties. Soluble starch used in pharmaceutical applications has undergone a purification procedure including washing steps. In this study, a lot of commercially available starch was divided into two parts. One was left intact and the other was subjected to an extra washing step. The two resulting lots were subjected to a series of physical characterization tests typical of those used to qualify raw materials. The two resulting lots gave virtually identical results from the tests. From the physical testing point of view, the two lots can be considered as two equivalent lots of the same excipient. However, when tested for their functionality when subjected to a compaction process, the two lots were found to be completely different. The compaction properties of the two lots were distinctly different under all environmental and processing conditions tested. From the functionality point of view, the two lots are two very different materials. The similar physical testing results but different functionality can be reconciled by considering the surface properties of the powders. It was found that the washing step significantly altered the surface energetic properties of the excipient. The washed lot consistently produced stronger compacts. These results are attributable to the measurably higher surface energy of induced by the additional washing step.

Theoretical and experimental considerations on the enthalpic relaxation of organic glasses using differential scanning calorimetry.

The enthalpy relaxation of amorphous salicin, used as model organic glass of pharmaceutical relevance, was investigated using a combination of DSC measurements and theoretical simulations. The combined approach makes it possible to discern between the effect of the glass forming properties of the material and the effects of the thermal history and experimental conditions. The approach also facilitates an unambiguous definition of the time scale of the experiment, such that objective comparison among relaxation time and glass transition temperature values can be made. The simulation provides accurate predictions of the DSC profiles obtained under a wide variety of experimental conditions. The effects of annealing time and the heating/cooling rate on the enthalpy recovery were explained by tracking the evolution of relaxation times as a function of temperature and time. The combined experimental and simulation approach also makes it possible to systematically explore the effect of specific glass forming properties, such as fragility and nonexponentiality, on the relaxation and associated thermal behavior of molecular organic glasses of pharmaceutical interest. To fully characterize these materials, it is necessary to go beyond the onset T(g) and include the early stages of the glass transition.

The effect of dehydration conditions on the functionality of anhydrous amorphous raffinose.

The purpose of this investigation is to study the effect of dehydration conditions of raffinose pentahydrate (RF.5H2O) on the physical properties and functionality of the resulting material. Crystalline RF.5H2O was dehydrated at two temperatures, 80 degrees C and 110 degrees C, producing the amorphous anhydrous form (RF.am). The dehydration temperature had no effect on a number of physical properties of the obtained RF.am, including X-ray powder diffraction, surface energy and water uptake. However, despite resulting on the same dynamics and extent of water sorption, different dehydration temperatures produced amorphous samples with drastically different recrystallization tendencies. Thermodynamic parameters show that despite the similarities on certain physical attributes, different dehydration temperature results in samples with significantly different free energy, hence stability. The difference in free energy produced by the dehydration temperature is attributed to differences in supramolecular structure that persist even in the liquid domain (above T(g)) of the amorphous samples. Evidence of such effects is observed as fluctuations in heat capacity present in RF.am but absent in the freshly prepared glass and also supported by the presence of molecular mobility modes observed using thermal polarization measurements.

A novel method for strict intranasal delivery of non-replicating RSV vaccines in cotton rats and non-human primates

Respiratory syncytial virus (RSV) is the most common viral cause of bronchiolitis and pneumonia in children twelve months of age or younger and a significant cause of lower respiratory disease in older adults. As various clinical and preclinical candidates advance, cotton rats (Sigmodon hispidus) and non-human primates (NHP) continue to play a valuable role in RSV vaccine development, since both animals are semi-permissive to human RSV (HRSV). However, appropriate utilization of the models is critical to avoid mis-interpretation of the preclinical findings. Using a multimodality imaging approach; a fluorescence based optical imaging technique for the cotton rat and a nuclear medicine based positron emission tomography (PET) imaging technique for monkeys, we demonstrate that many common practices for intranasal immunization in both species result in inoculum delivery to the lower respiratory tract, which can result in poor translation of outcomes from the preclinical to the clinical setting. Using these technologies we define a method to limit the distribution of intranasally administered vaccines solely to the upper airway of each species, which includes volume restrictions in combination with injectable anesthesia. We show using our newly defined methods for strict intranasal immunization that these methods impact the immune responses and efficacy observed when compared to vaccination methods resulting in distribution to both the upper and lower respiratory tracts. These data emphasize the importance of well-characterized immunization methods in the preclinical assessment of intranasally delivered vaccine candidates.