Niraj S. Trasi

Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin

ABSTRACTPurposeTo gain a better understanding of the physical state and the unusual thermal behavior of milled griseofulvin.MethodsGriseofulvin crystals and amorphous melt quench samples were milled in a vibrating ball mill for different times and then analyzed using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Modulated DSC (mDSC) and annealing studies were done for the milled amorphous samples to further probe the effects of milling.ResultsMilling of griseofulvin crystals results in decrease in crystallinity and amorphization of the compound. A double peak is seen for crystallization in the DSC, which is also seen for the milled melt quench sample. Both enthalpy and temperature of crystallization decrease for the milled melt quenched sample. Tg is visible under the first peak with the mDSC, and annealing shows that increasing milling time results in faster crystallization upon storage.ConclusionMilling of griseofulvin results in the formation of an amorphous form and not a mesophase. It increases the amount of surface created and the overall energy of the amorphous griseofulvin, which leads to a decreased temperature of crystallization. The two exotherms in the DSC are due to some particles having nuclei on the surface.

Effect of polymers on nucleation and crystal growth of amorphous acetaminophen

While some organic molecules readily form a glass on cooling from the melt, others undergo crystallization. In this study, the underlying reason for the good glass forming ability of acetaminophen upon cooling of the melt was investigated. The impact of polymers on the crystal nucleation and growth of supercooled acetaminophen was also probed. The good glass forming ability of acetaminophen was ascribed to a separation in temperature where rapid nucleation and rapid growth occurred. Poly(acrylic acid) (PAA) and poly(vinyl pyrrolidone) (PVP) were the most effective polymers at inhibiting crystal growth. These polymers were also observed to form hydrogen bonds with acetaminophen based on infra-red spectroscopy. However, PAA was found to increase the nucleation rates while HPMCAS, which had little effect on growth, was the most effective polymer at reducing nucleation. Thus it appears that polymers can stabilize a drug in the amorphous state either by reducing crystal nucleation and/or growth. An investigation of the mechanism of stabilization is therefore important for choosing the right polymer to produce robust amorphous systems.

Impact of surfactants on the crystal growth of amorphous celecoxib

The purpose of this study was to investigate the impact of surfactants on the rate of crystal growth of amorphous celecoxib, both in the presence and absence of a polymer. Celecoxib is a poorly water-soluble non-steroidal anti-inflammatory drug. Such compounds may be formulated as amorphous solid dispersions to improve bioavailability, and solid dispersions can contain both a surfactant and a polymer. While the impact of polymers on crystal growth rates has been studied, the effect of surfactants is largely unexplored. Herein, the effect of sodium lauryl sulfate (SLS), sucrose palmitate and d-α tocopherol polyethylenglycol 1000 succinate (TPGS) at a 10% (w/w) concentration on the crystal growth rate of celecoxib was investigated. Linear crystal growth rates as a function of temperature (70-120 °C) were measured using optical microscopy. The mixtures were characterized using differential scanning calorimetry (DSC), infrared spectroscopy, and X-ray diffraction. The results indicate that the surfactants increase the crystal growth rate of amorphous celecoxib. However, addition of polyvinyl pyrrolidone (PVP) helped to mitigate the increase in growth rates, although the ternary systems were highly complex. Thus it is clear that the impact of a surfactant on the physical stability of an amorphous solid dispersion should be considered during formulation.

Factors influencing crystal growth rates from undercooled liquids of pharmaceutical compounds.

Amorphous forms of drugs are increasingly being used to deliver poorly water-soluble compounds. Therefore, understanding the magnitude and origin of differences in crystallization kinetics is highly important. The goal of this study was to better understand the factors that influence crystal growth rates from pharmaceutically relevant undercooled liquids and to evaluate the range of growth rates observed. The crystal growth rates of 31 drugs were determined using an optical microscope in the temperature region between the glass transition temperature (Tg) and the melting temperature (Tm). Thermodynamic parameters such as Tm, melting enthalpy, and Tg were determined using a differential scanning calorimeter (DSC). Selected viscosity values for the undercooled liquid were taken from the literature. The growth rates of the different compounds were found to be very different from each other with a variation of about 5 orders of magnitude between the fastest growing compounds and the slowest growing compounds. A comparison of the physicochemical properties showed that compounds that had fast crystal growth rates had smaller molecular weights, higher melting temperatures, lower melt entropies, lower melt viscosities, and higher crystal densities. Variations in the growth rates of the compounds could be rationalized to a large extent by considering the thermodynamic driving force for crystallization, the viscosity, and the entropy difference between the melt and undercooled liquid. This study therefore provides important insight into factors that may compromise the stability of amorphous pharmaceuticals.

Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds

The purpose of this work was to determine what aspect of the milled compound influences its thermal profile. For this, six different compounds with different properties were chosen and cryomilled for different times to get an amorphous solid. Differential scanning calorimetry (DSC) and X-ray powder diffraction were used to characterize the material and look at the thermal behavior. Melt-quenched samples were also prepared, and the thermal profile upon milling was determined and correlated with the thermal behavior of the cryomilled samples. Growth rates were determined by hot-stage microscopy. Ketoconazole, when cryomilled, showed only one crystallization exotherm in the DSC profile. Ursodiol, and to some extent indomethacin, initially showed a double exotherm which eventually become a single exotherm on further milling. Griseofulvin, carbamazepine, and piroxicam exhibited a double exotherm in the DSC profile upon cryomilling to the amorphous state. Surface crystal growth rates around Tg were found to be highest for compounds showing the double exotherm in the DSC. Thus, it was seen that compounds which have high surface crystallization tendency will exhibit the double exotherm during heating.

Dissolution performance of binary amorphous drug combinations--Impact of a second drug on the maximum achievable supersaturation.

An increased number of amorphous formulations of poorly water soluble drugs are being introduced into the market due to their higher transient solubility and thus faster absorption and higher bioavailability. While most amorphous drug products contain a single drug substance, there is a growing trend towards co-formulating compounds in the same dosage form to improve patient compliance. The purpose of the present work was to evaluate the dissolution behavior and maximum achievable solution concentrations of amorphous solid dispersions of co-formulated ritonavir and lopinavir, and to compare the results with individual amorphous solid dispersion formulations. Dispersions of ritonavir and lopinavir were prepared in polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose acetate succinate (HPMCAS) at a 20% (w/w) total drug loading, both alone and in combination, at three different lopinavir:ritonavir weight ratios. Amorphous films containing both drugs, but no polymer, were also prepared. The dissolution behavior of the dispersions and the amorphous films in non-sink conditions was evaluated, using ultracentrifugation to separate any colloidal material from molecularly dissolved drug. Nanoparticle tracking analysis was used to characterize colloidal material formed during the dissolution process. Results from the dissolution study revealed that, although supersaturated solutions resulted following dissolution, the maximum achievable concentration of each drug, when present in combination, was dramatically lower than when the individual dispersions were dissolved. The maximum achievable solution concentration for systems containing both drugs was found to decrease as the mole fraction of the drug in the amorphous phase decreased. The type of polymer used to formulate the dispersion also appeared to influence the dissolution behavior whereby the HPMCAS dispersions dissolved rapidly, resulting in the generation of a nanodroplets, while the PVP dispersions did not produce as many colloidal species. These results highlight the need to consider potential decreases in achievable supersaturation for formulations containing more than one amorphous compound.

Finding the Needle in the Haystack: Characterization of Trace Crystallinity in a Commercial Formulation of Paclitaxel Protein-Bound Particles by Raman Spectroscopy Enabled by Second Harmonic Generation Microscopy

Second harmonic generation (SHG) microscopy was used to rapidly identify regions of interest for localized confocal Raman spectroscopy measurements in order to quantify crystallinity within lyophilized Abraxane powder (protein bound paclitaxel for injectable suspension). Water insoluble noncentrosymmetric crystalline particles ranging from ∼1 to 120 μm were identified by SHG, with wide variability in crystal size and frequency observed between several batches of Abraxane. By targeting the Raman analysis to these localized regions identified by SHG, the required measurement time was decreased over 2 orders of magnitude, from 8 h to 2 s. Experimental Raman spectra of SHG active domains in Abraxane were in good agreement with experimental spectra of pure crystalline paclitaxel. These collective results are consistent with up to 30% of the active ingredient being present as poorly soluble crystalline particulates in some batches of Abraxane.

Investigating the effect of dehydration conditions on the compactability of glucose.

Hydrates are commonly found in pharmaceutical ingredients either in excipients or in the active pharmaceutical ingredient form. There is always the possibility that the processing involved in manufacturing can result in the dehydration of the hydrate components. It has been seen that different dehydration conditions can have an effect on the behavior of the final product; however this area has not been fully investigated. In this work, glucose monohydrate powder was dehydrated at four different conditions and then compressed to see the effect on the hardness of the compacts. Various analytical tools such as inverse gas chromatography, differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy were used to determine any differences in the properties of the dehydrates and correlated with the obtained compact hardness. Annealing studies were performed to determine the effect of storage on the dehydrated materials both before and after compression. It was observed that while annealing of the powders did have an impact, annealing of the compacts did not influence the hardness. The results of the characterization and annealing studies showed that the difference in the behavior of glucose dehydrates were due to the presence of amorphous regions within the particulates.

Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen

The nucleation behaviour of supersaturated acetaminophen was studied in the presence and absence of pharmaceutical polymers. Two different techniques involving turbidimetry and particle count analysis were used. Poly(vinylpyrrolidone) and the cellulosic polymers were found to be the most effective at nucleation inhibition at the supersaturation studied.

Nucleation and crystal growth of amorphous nilutamide – unusual low temperature behavior

Crystallization from organic undercooled melts is an important topic of investigation, in particular for pharmaceuticals. Nilutamide, a small organic molecule used to treat prostrate cancer, was found to exhibit interesting glass forming and crystallization behavior. Nilutamide readily formed an amorphous solid following melt quenching, despite having a very high crystal growth rate. The good glass forming ability of this compound was attributed to its reluctance to nucleate. Interestingly, when samples were cooled to deep within the glassy region, nucleation to a previously unreported metastable polymorph was observed. Surprisingly, nucleation was found to be more likely when samples were held far below the glass transition temperature (Tg) than when annealed above the Tg. At higher temperatures, the stable polymorph was observed to have the faster growth rate, while at low temperatures, the metastable form grew faster. Conformational analysis suggests that the stable crystal form contains a higher energy conformer which may explain the slow nucleation from the supercooled melt as well as the cross-over in the growth rates of the stable and metastable polymorphs at lower temperatures. This study highlights the complex crystallization behavior of organic supercooled liquids and glasses.