Stability of Rapidly Crystallizing Sulfonamides Glasses by Fast Scanning Calorimetry: Crystallization Kinetics and Glass-Forming Ability.

Production and evaluation of the kinetic stability of the amorphous forms of active pharmaceutical ingredients are among the current challenges of modern pharmaceutical science. In the present work, amorphous forms of several sulfonamides were produced for the first time using Fast Scanning calorimetry. The parameters, characterizing the glass-forming ability of the compounds, i.e. the critical cooling rate of the melt and the kinetic fragility, were determined. The cold crystallization kinetics was studied using both isothermal and non-isothermal approaches. The results of the present study will contribute to the development of approaches for producing amorphous forms of rapidly crystallizing active pharmaceutical ingredients.

Crystallization kinetics and glass-forming ability of rapidly crystallizing drugs studied by Fast Scanning Calorimetry.

The use of the amorphous forms of drugs is a modern approach for the enhancement of bioavailability. At the same time, the high cooling rate needed to obtain the metastable amorphous state often prevents its investigation using conventional laboratory methods such as differential scanning calorimetry, X-ray powder diffractometry. One of the ways to overcome this problem may be the application of Fast Scanning Calorimetry. This method allows direct determination of the critical cooling rate of the melt and kinetic parameters of the crystallization for bad glass formers. In the present work, the amorphous states of dopamine hydrochloride and atenolol were created using Fast Scanning Calorimetry for the first time. Critical cooling rates and glass transition temperatures of these drugs were determined. Based on the values of the kinetic fragility parameter, dopamine hydrochloride glass can be considered strong, while atenolol glass is moderately strong. Both model-based and model-free approaches were employed to determine the kinetic parameters of cold crystallization of dopamine and atenolol. The results were compared with the data from isothermal crystallization experiments. The Nakamura crystallization model provides the best description of the crystallization process and can be used to predict the long term stability of the amorphous forms of the drugs. The presented approaches may find applications in predicting the storage time and choosing the optimal storage conditions of the amorphous drugs prone to crystallization.

Kinetic stability of amorphous dipyridamole: A fast scanning calorimetry investigation.

One of the main tasks of modern pharmaceutics is enhancing the solubility of drugs. The approaches for solving this problem include producing active pharmaceutical ingredients in the amorphous state. However, the use of amorphous drugs requires the determination of their kinetic stability. The latter is often assessed using isothermal techniques, which are time-consuming. Alternatively, non-isothermal methods can be employed, allowing to determine the kinetic triplet more rapidly. Also, such techniques can be used to develop predictive models for storage stability. The production of the amorphous state itself typically requires fast cooling rates, which may not be easily accessible. Fast scanning calorimetry is a promising tool for the investigation of amorphous drug systems. In the present work, the crystallization of the model drug dipyridamole was investigated using the fast scanning calorimetry method. The kinetic stability of the amorphous form of the drug was evaluated using both, isothermal and non-isothermal methods. The Nakamura crystallization model was found to be applicable for the prediction of the temporal stability of the amorphous drug forms. The obtained results may find applications in the investigation of the kinetic stability of amorphous drug systems.

Kinetic stability of amorphous solid dispersions with high content of the drug: A fast scanning calorimetry investigation.

Formation of amorphous solid dispersions is an effective way to enhance the bioavailability of drugs. One of the main disadvantages of such systems is their low storage stability. Estimation and prognosis of storage stability of the amorphous solid dispersions are possible through modeling of the kinetics of crystallization by the Arrhenius equation and the resulting parameters, i.e., activation energy and pre-exponential factor. These parameters can be determined using the non-isothermal kinetics methods based on both model-fitting and model-free approaches using the differential scanning calorimetry data. In the present work, the formation of amorphous solid dispersions of the phenacetin model drug with polyvinylpyrrolidone of different molecular masses (3500-1.3 × 106 g·mol-1) was studied in a wide range of heating and cooling rates. The kinetic parameters of the crystallization process of the active pharmaceutic ingredient in the solid dispersions with increased drug content were determined. The dependence of the kinetic parameters of phenacetin cold crystallization on the molecular weight of the polymer is non-linear. The approaches used in the present work can find applications for the estimation of kinetic stability of amorphous pharmaceutical systems prone to crystallization.

Hypoplastic left heart syndrome: factors influencing therapeutic choice.

Parent's choices among therapeutic options for their infants born with hypoplastic left heart syndrome are difficult and controversial. Currently, management options include surgical reconstruction, cardiac transplantation, and comfort measures only. We retrospectively reviewed medical records of 47 patients (1989-1999) to create a database of clinical features of infants who received either an operation or comfort care only. Eleven families were interviewed by means of a structured questionnaire pertaining to their experience and reasons for their choice. Of the 47, 20 were prenatally diagnosed and nine of these (45%) aborted. The remaining 38 of the 47 were liveborns. Of the 38, 20/38 (53%) chose comfort care only. The other 18 chose operation. Although 17 were able to survive until first stage repair, only 8/17 (47%) survived beyond five months. At the time of last contact (ages one to 4.5 years), 5/17 (29%) remained alive. Over the nine years an increasing proportion of parents chose operative reconstruction; 8/11 (73%) for 1996-99 vs 10/27 (37%) for 1989-1995. Interviewed families who chose comfort care were more likely to believe the rate of survival following operation was poor, quality of life was diminished, and seemed concerned that their infant would suffer. Influence by optimistic physicians at surgical centers seemed important for an operative choice. Most suggested that provision of written materials, professional family counseling, and support groups of hypoplastic left heart syndrome families are or would be helpful.

Volkmann's ischemic contracture. A case report.

A case is presented illustrating some of the basic principles in the development and repair of Volkmann's ischemic contracture following a supracondylar fracture. The etiology, initial signs, prevention, and possible treatments of the contracture are discussed. Early fasciotomy is the best treatment for impending contracture, while neurolysis with infarct excision, a flexor pronator slide, and tendon transfer can return much function following established contracture of the forearm.