Use of Resonant Acoustic Mixing Technology for Ultra-Low-Dose Blending in a Single-Step Mixing Process.

PURPOSE: To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization. METHODS: Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends. RESULTS: Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 µg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 µg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250-10 mg sample (125-5 µg CAF). L1 BU criteria only failed at the level of 2 µg CAF, despite target precision to 26 nanograms (98.7% label claim). CONCLUSIONS: This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF.

The study of phase separation in amorphous freeze-dried systems. Part I: Raman mapping and computational analysis of XRPD data in model polymer systems.

Phase separation in amorphous freeze-dried mixtures is likely in many systems. However, suitable detection methodology has been lacking, as the classical technique, differential scanning calorimetry (DSC), relies upon detection of multiple glass transition temperatures (T(g)), each of which is characteristic of a given amorphous phase. The lack of a detectable glass transition temperature in protein-rich phases, limits the application of DSC. Here, we focus on evaluating new methods for detection of phase separation in amorphous freeze-dried mixtures. A novel Raman mapping technique has been evaluated using model binary polymer mixtures of PVP and dextran known to phase separate. The sensitivity of this Raman technique in detecting phase separation was comparable to DSC. Phase separation was detected in compositions of 1:9 to 3:2 (PVP 10,000/dextran 5000) and 3:7 to 4:1 (PVP 29,000/dextran 10,000) by DSC and Raman. Computational methodologies applied to X-ray powder diffraction (XRPD) data from these systems are also shown to reliably detect the presence of phase separation. However, some differences between techniques were observed in cases lying on the boundary of phase separation. Thus, Raman and XRPD show promise for detecting phase separation in systems, which do not exhibit detectable glass transitions by calorimetry.

Effect of water vapor sorption on local structure of poly(vinylpyrrolidone).

The effect of water vapor sorption on the local structure of poly(vinylpyrrolidone) (PVP), was investigated using high-quality X-ray powder diffraction (XRPD). To examine the effects on molecular scale structure due to polymer chain length and water sorption, different molecular weights of PVP were studied at ambient temperature and different controlled relative humidities. Sorption of water determined gravimetrically on drying and changes to the glass-transition temperature (T(g)) measured by modulated differential scanning calorimetry (mDSC) were found to be consistent with previous reports. The XRPD results show that the position of the high- and low-angle halos for PVP change with the sorption of water. The corresponding characteristic scattering distances display a strong correlation with the measured water content and to T(g). Chemometric analysis was also performed to extract water content information from XRPD data and obtained results are correlated with the values measured gravimetrically, which lends support for the apparent clustering of water in PVP drawn by other techniques.

A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion.

A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates.

Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction.

Recognizing limitations with the standard method of determining whether an amorphous API-polymer mixture is miscible based on the number of glass transition temperatures (T(g)) using differential scanning calorimetry (DSC) measurements, we have developed an X-ray powder diffraction (XRPD) method coupled with computation of pair distribution functions (PDF), to more fully assess miscibility in such systems. The mixtures chosen were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran, both prepared by lyophilization; and indomethacin-PVP, prepared by evaporation from organic solvent. Immiscibility is detected when the PDF profiles of each individual component taken in proportion to their compositions in the mixture agree with the PDF of the mixture, indicating phase separation into independent amorphous phases. A lack of agreement of the PDF profiles indicates that the mixture with a unique PDF is miscible. In agreement with DSC measurements that detected two independent T(g) values for the dextran-PVP mixture, the PDF profiles of the mixture matched very well indicating a phase separated system. From the PDF analysis, indomethacin-PVP was shown to be completely miscible in agreement with the single T(g) value measured for the mixture. In the case of the trehalose-dextran mixture, where only one T(g) value was detected, however, PDF analysis clearly revealed phase separation. Since DSC can not detect two T(g) values when phase separation produces amorphous domains with sizes less than approximately 30 nm, it is concluded that the trehalose-dextran system is a phase separated mixture with a structure equivalent to a solid nanosuspension having nanosize domains. Such systems would be expected to have properties intermediate to those observed for miscible and macroscopically phase separated amorphous dispersions. However, since phase separation has occurred, the solid nanosuspensions would be expected to exhibit a greater tendency for physical instability under a given stress, that is, crystallization, than would a miscible system.

Analysis of amorphous and nanocrystalline solids from their X-ray diffraction patterns.

PURPOSE: The purpose of this paper is to provide a physical description of the amorphous state for pharmaceutical materials and to investigate the pharmaceutical implications. Techniques to elucidate structural differences in pharmaceutical solids exhibiting characteristic X-ray amorphous powder patterns are also presented. MATERIALS AND METHODS: The X-ray amorphous powder diffraction patterns of microcrystalline cellulose, indomethacin, and piroxicam were measured with laboratory XRPD instrumentation. Analysis of the data were carried out using a combination of direct methods, such as pair distribution functions (PDF), and indirect material modeling techniques including Rietveld, total scattering, and amorphous packing. RESULTS: The observation of X-ray amorphous powder patterns may indicate the presence of amorphous, glassy or disordered nanocrystalline material in the sample. Rietveld modeling of microcrystalline cellulose (Avicel PH102) indicates that it is predominantly disordered crystalline cellulose Form Ibeta with some amorphous contribution. The average crystallite size of the disordered nanocrystalline cellulose was determined to be 10.9 nm. Total scattering modeling of ground samples of alpha, gamma, and delta crystal forms of indomethacin in combination with analysis of the PDFs provided a quantitative picture of the local structure during various stages of grinding. For all three polymorphs, with increased grinding time, a two-phase system, consisting of amorphous and crystalline material, continually transformed to a completely random close packed (RCP) amorphous structure. The same pattern of transformation was detected for the Form I polymorph of piroxicam. However, grinding of Form II of piroxicam initially produced a disordered phase that maintained the local packing of Form II but over a very short nanometer length scale. The initial disordered phase is consistent with continuous random network (CRN) glass material. This initial disordered phase was maintained to a critical point when a transition to a completely amorphous RCP structure occurred. CONCLUSIONS: Treating X-ray amorphous powder patterns with different solid-state models, ranging from disordered nanocrystalline to glassy and amorphous, resulted in the assignment of structures in each of the systems examined. The pharmaceutical implications with respect to the stability of the solid are discussed.