Igor Ivanisevic

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.

Evaluation of Drug-Polymer Miscibility in Amorphous Solid Dispersion Systems

ABSTRACTPurposeTo evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA).Materials and MethodsAmorphous solid dispersion samples were prepared at different drug-to-polymer ratios and analyzed using differential scanning calorimetry (DSC), mid-infrared (IR) spectroscopy, and powder X-ray diffractometry (PXRD). To help with interpretation of the IR spectra, principal components (PC) analysis was performed. Pair Distribution Functions (PDFs) of the components in the dispersion were determined from the PXRD data, and the pure curves of the components were also extracted from PXRD data using the Pure Curve Resolution Method (PCRM) and compared against experimentally obtained results.ResultsMolecular-level mixing over the complete range of concentration was verified for nifedipine-PVP and felodipine-PVP. For felodipine-PAA, drug-polymer immiscibility was verified for samples containing 30 to 70% polymer, while IR results suggest at least some level of mixing for samples containing 10 and 90% polymer. For ketoconazole-PVP system, partial miscibility is suspected, whereby the presence of one-phase amorphous solid dispersion system could only be unambiguously verified at higher concentrations of polymer.ConclusionsThe three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.

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.

Novel methods for the assessment of miscibility of amorphous drug‐polymer dispersions

A typical approach to miscibility analysis of amorphous drug-excipient dispersions involves measuring the glass transition temperature, T(g), using differential scanning calorimetery (DSC). Recently, we discussed two computational methods for the miscibility analysis of amorphous dispersions using X-ray powder diffraction (XRPD). Those methods could be used to qualify an amorphous dispersion as miscible or phase separated, with the implication that miscible dispersions are more stable towards recrystallization. The methods were limited by the need for reference XRPD patterns of both the amorphous drug and excipient. In this work, we propose two additional computational approaches that overcome that limitation and can be used to quantify the degree of miscibility in an amorphous dispersion. The first approach is based on the use of a Pure Curve Resolution Method to extract unknown amorphous references as well as qualify miscibility. The second method, based on Alternate Least Squares, can then be used to quantify the degree of miscibility by determining the nearest neighbor (NN) coordination number for the active pharmaceutical ingredient (API) and excipient. It is proposed that the NN coordination number is related to physical stability.

Physical Stability Studies of Miscible Amorphous Solid Dispersions

Physical stability of 12 amorphous solid dispersions was evaluated over 9-22 months under ambient conditions using X-ray powder diffraction. The nine dispersions initially characterized as miscible drug-polymer systems all remained X-ray amorphous for the duration of their respective studies. In contrast, the three phase-separated systems all crystallized in 1-2 months, while the pure amorphous active pharmaceutical ingredients used in this study all crystallized within a few days, under the conditions of this study. Changes in the local order of dispersions that included polyvinylpyrrolidone were observed and appeared to correlate to periods of higher relative humidity (RH), reverting back to the original local order as the RH decreased. Phase-separation in the miscible dispersions as a result of ambient RH conditions did not appear to take place. Finally, formation of pores (voids) was observed through small-angle X-ray powder diffraction during crystallization of one model drug (felodipine).

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.

Operating in configuration space significantly improves human performance in teleoperation

Discusses the use of configuration space (C-space) as a means of visualization and control in teleoperation of robot arm manipulators. The motivation is to improve operator performance in tasks involving manipulator motion in a complex three-dimensional (3D) environment with obstacles. Unlike other motion planning tasks, operators are known to make expensive mistakes in arm control, due to deficiencies of human spatial reasoning. The advantage of C-space is that in it the arm becomes a point, a case which humans are much better equipped to handle. To make such operation possible, a tool is proposed that reduces motion in 3D C-space to that in 2D C-space. It is then shown on results from testing 18 human subjects that translating the problem of a three-link 3D arm manipulator motion into C-space improves the operator performance remarkably, by a factor of 2 to 4, compared to usual work space control.

A human-machine interface for teleoperation of arm manipulators in it complex environment

Discusses the feasibility of using configuration space (C-space) as a means of visualization and control in operator-guided real-time motion of a robot arm manipulator. The motivation is to improve performance of the human operator in tasks involving the manipulator motion in an environment with obstacles. Unlike some other motion planning tasks, operators are known to make expensive mistakes in such tasks, even in a simpler two-dimensional case. Using an example of a two-dimensional arm manipulator, we show that translating the problem into C-space improves the operator performance remarkably, on the order of magnitude compared to the usual work space control.

Augmenting human performance in motion planning tasks-the configuration space approach

The paper is concerned with the development of methods that can be used to augment human performance in three degree of freedom (DOF) motion planning tasks. Previous experimental studies have shown that human performance in such motion planning tasks is inadequate, especially when complex objects and/or environments are involved. Our approach is based on the use of configuration space (C-Space) to simplify the motion planning task from that of moving a complex object in work space (W-space) to moving a point in a C-space maze. Tools are developed which allow the user to easily grasp all the information contained in 3D C-space and use it to solve the task at hand.

Testing human performance in motion planning over the Internet

This paper describes a novel approach to the study of human performance in motion planning for complex objects. The proposed approach is based on an anonymous operation over the Internet. A system useful in conducting these types of studies is developed and applied in a study of human performance in the use of the configuration space (C-space) method of teleoperation. Results of this study are presented with the conclusion that the C-space method of teleoperation is suitable for most subjects and significant improvements in performance can be expected when utilizing the C-space over traditional work space control.