Modulating the dehydration conditions of adefovir dipivoxil dihydrate to obtain different physical forms of anhydrate.

The physical form of anhydrous adefovir dipivoxil (AD), obtained following the dehydration of AD dihydrate, was governed by the kinetics of water removal. The rate and extent of water removal following the dehydration of AD dihydrate was manipulated by altering the sample size, pan configuration, and heating rate in a differential scanning calorimeter. Interestingly, when there was moderate resistance to water removal, a new anhydrous polymorph (melting point 80°C) was obtained. High resistance to water removal resulted in amorphous AD. Variable temperature XRD of AD provided direct and unambiguous evidence of this new polymorph. We have prepared and characterized this new anhydrous polymorph as well as amorphous AD. Based on HPLC, AD dihydrate heated under different conditions in the DSC was observed to be chemically stable. When exposed to water vapor (RH ≥ 80%; 25°C), the new polymorph had a stronger propensity to convert to AD dihydrate than the amorphous anhydrate or AD form I.

Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility.

Physical instability of amorphous solid dispersions can be a major impediment to their widespread use. We characterized the molecular mobility in amorphous solid dispersions of itraconazole (ITZ) with each polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) with the goal of investigating the correlation between molecular mobility and physical stability. Dielectric spectra showed two mobility modes: α-relaxation at temperatures above the glass transition temperature (Tg) and ß-relaxation in the sub-Tg range. HPMCAS substantially increased the α-relaxation time, with an attendant increase in crystallization onset time and a decrease in crystallization rate constant, demonstrating the correlation between α-relaxation and stability. The inhibitory effect on α-relaxation as well as stability was temperature dependent and diminished as the temperature was increased above Tg. PVP, on the other hand, affected neither the α-relaxation time nor the crystallization onset time, further establishing the link between α-relaxation and crystallization onset in solid dispersions. However, it inhibited the crystallization rate, an effect attributed to factors other than mobility. Interestingly, both of the polymers acted as plasticizers of ß-relaxation, ruling out the latter's involvement in physical stability.

Molecular motions in sucrose-PVP and sucrose-sorbitol dispersions-II. Implications of annealing on secondary relaxations.

PURPOSE: To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions. METHODS: Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy. RESULTS: In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for ß1- (the slower relaxation) but not for ß2-relaxations. The effect of annealing on ß2-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both ß1- and ß2-relaxations. CONCLUSIONS: An increase in local mobility of sucrose brought about by annealing could be negated with an additive.

Controlling the physical form of mannitol in freeze-dried systems.

A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6·0.5H2O) in the lyophile. Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components. If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability. We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying. When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol. Based on low temperature X-ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures ≤ -20 °C, while anhydrous mannitol crystallized at temperatures ≤ -10 °C. The transition temperature (anhydrate - MHH) appears to be ∼-15 °C. The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ∼-5 °C. Thus, ice crystallization followed by annealing at temperatures ≤ -10 °C can be an effective strategy to prevent MHH formation.

Molecular mobility as a predictor of the water sorption by annealed amorphous trehalose.

PURPOSE: The work aims at investigating the correlation of water sorption potential with different measures of molecular mobility in an annealed amorphous model compound (trehalose). METHODS: Amorphous trehalose, prepared by freeze-drying, was annealed at 100°C (17°C < T (g)) for up to 120 h. Global molecular mobility was studied using a broadband dielectric spectrometer in the frequency range of 10(6)-10(-2) Hz. Enthalpic recovery was measured by differential scanning calorimetry and water sorption profiles were obtained using an automated vapor sorption balance. RESULTS: As a function of annealing time, there was an increase, both in average α-relaxation time and enthalpic recovery and a decrease in the amount of sorbed water. A strong linear correlation was observed between the water sorption potential and the dielectric relaxation time, indicating a common underlying mechanism of the effect of annealing time on these properties. Enthalpic recovery, which is widely used as a measure of structural relaxation, did not correlate well with the extent of water sorption. CONCLUSIONS: The α-relaxation time can be used as a predictor of the water sorption potential of amorphous trehalose. It will be of interest and value to develop such predictive models for other amorphous compounds of pharmaceutical interest.

Correlation between molecular mobility and physical stability of amorphous itraconazole.

The goal was to investigate the correlation between molecular mobility and physical stability in amorphous itraconazole and identify the specific mobility mode responsible for its instability. The molecular mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5-40 °C temperature range revealed a ß-relaxation which exhibited Arrhenius temperature dependence. As the temperature approached T(g), ß-relaxation became progressively less resolved due to interference from the high frequency tail of the α-relaxation and then transformed into an excess wing. Above T(g), nonlinear temperature dependence of the α-relaxation was described by the Vogel-Tammann-Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ∼4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 °C, was best described by the 3-dimensional nucleation and growth model. Primary relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above T(g) as indicated by the linear correlation of α-relaxation with both crystallization onset and kinetics (represented by the inverse of the crystallization rate constant). A strong coupling between global mobility and crystallization onset was evident. However, for growth kinetics, the coupling was less pronounced, indicating the involvement of factors other than global mobility.

Molecular mobility as an effective predictor of the physical stability of amorphous trehalose.

Amorphous trehalose was prepared by different methods, viz., freeze-drying, spray-drying and dehydration of trehalose dihydrate. The different molecular relaxations were characterized by dynamic dielectric spectroscopy. The preparation method significantly affected the structural relaxation time and its temperature dependence in the glassy region. The order of activation energy for α-relaxation was spray-dried > freeze-dried > dehydrated. However, the secondary relaxation times remained essentially unaffected by the preparation method. Isothermal crystallization kinetics was studied at several temperatures above the glass transition temperature (T(g)). A linear correlation was observed between the crystallization time (inverse of crystallization rate constant) and the average α-relaxation time, suggesting a similar molecular origin for these two processes. There was also strong coupling of the crystallization onset time with global molecular mobility in the supercooled liquid region, enabling the development of predictive models. The observed experimental onset times were in excellent agreement with the predicted values at temperatures around and below T(g).

Use of dielectric spectroscopy to monitor molecular mobility in glassy and supercooled trehalose.

Dielectric spectroscopy was used to comprehensively characterize the molecular mobility in amorphous trehalose, an extensively used bioprotective agent. Isothermal frequency sweeps were carried out at different temperatures in the glassy and supercooled liquid states of freeze-dried trehalose. Two previously reported secondary relaxations were observed at temperatures far below its glass transition temperature (T(g)). At temperatures close to T(g), removal of dc conductivity contribution revealed a relaxation peak. The origin of this peak was evaluated using several diagnostic tests and determined to be the α-relaxation. There was also an excess wing in the high-frequency tail of α-relaxation. Sub-T(g) annealing caused the primary relaxation to shift to lower frequencies, enabling resolution of the excess wing, which was characterized to be the true Johari-Goldstein (JG) relaxation. A qualitatively similar effect of annealing on JG relaxation was also observed. The average relaxation times of the two previously reported secondary relaxations were unaffected by annealing.

Subtraction of DC conductivity and annealing: approaches to identify Johari-Goldstein relaxation in amorphous trehalose.

Amorphous trehalose finds extensive use as a stabilizer of biomolecules including proteins and phospholipids. Hypothesizing that molecular mobility is a determinant of its stability, dynamic dielectric spectroscopy (DDS) was used to map the different modes of mobility. Isothermal dielectric relaxation profiles of amorphous trehalose were obtained, over the frequency range of 10(-1)-10(7) Hz, and at temperatures ranging from 30-170 °C. At temperatures close to the glass transition (T(g)), the α-relaxation was not readily discernible due to interference from dc conductivity. We used Kramers-Kronig transformation that enabled not only the complete resolution of α-relaxation but also the identification of an excess wing, in the high frequency tail of α-relaxation. On annealing, this excess wing developed into a partially resolved and hitherto unidentified ß-relaxation peak. This peak, due to its position in the dielectric spectrum, its annealing time dependence and the good agreement with the calculated independent relaxation time, was assigned to the Johari-Goldstein process. This work demonstrates the utility of conductivity subtraction coupled with sub-T(g) annealing to successfully study all the modes of mobility in amorphous trehalose. This approach can potentially be extended to situations wherein dc conductivity impedes the complete characterization of molecular mobility.

Monitoring phase transformations in intact tablets of trehalose by FT-Raman spectroscopy.

The purpose of this study is to monitor phase transformations in intact trehalose tablets using FT-Raman spectroscopy. Tablets of trehalose dihydrate, amorphous trehalose (obtained by freeze-drying aqueous trehalose solutions), and anhydrous trehalose (beta-trehalose) were prepared. The tablets were exposed to different conditions [11% and 0% RH (60 degrees C); 75% RH (25 degrees C)] and monitored periodically over 96 h using Raman spectroscopy. Within 96 h of storage, the following phase transformations were observed: (1) trehalose dihydrate-->beta-trehalose (11% RH, 60 degrees C), (2) trehalose dihydrate-->alpha-trehalose (0% RH, 60 degrees C), (3) beta-trehalose-->trehalose dihydrate (75% RH, 25 degrees C), and (4) amorphous trehalose-->trehalose dihydrate (75% RH, 25 degrees C). FT-Raman spectroscopy was a useful technique to identify the solid form and monitor multiple-phase transformations in intact trehalose tablets stored at different conditions.