M. E. Brown

The thermal and photostability of solid pharmaceuticals

Drugs degrade to different extents on separate exposure to heat, moisture, oxidation and light. Combination of these stresses causes very complex behaviour. Many studies have been reported of the thermal behaviour of drugs in the solid-state, but most of the information available on the photodegradation of drugs refers to reactions in solution, (usually aqueous) and photoreactions in the solid-state are even more complex. In drug formulations, the presence of excipients adds further complications because the excipients may increase, have no effect on, or decrease the inherent stabilities of the drug. The literature has been explored to review the thermal and photostabilities of solid pharmaceuticals.

The thermal stability of triprolidine hydrochloride and its mixtures with cyclodextrin and glucose

Triprolidine hydrochloride (C19H22N2·HCl·H2O) (TPH) is a well-known antihistamine drug which is reported as being photosensitive. The thermal stabilities of TPH and of 1:1 molar and 1:1 mass ratio physical mixtures of TPH with β-cyclodextrin (BCD) and with glucose have been examined using DSC, TG and TG-FTIR, complemented by X-ray powder diffraction (XRD) and infrared spectroscopic (IR) studies. Thermal studies of the solid TPH/BCD mixtures indicated that interaction between the components occurs and it is possible that the TPH molecule may be least partially accommodated in the cavity of the BCD host molecule. XRD results support this indication of inclusion. The results of molecular modelling suggest that TPH is most likely to be accommodated in the BCD cavity as a neutral triprolidine molecule with the toluene portion of the molecule preferentially included in the cavity. The results obtained illustrate the general stability of TPH. The study has also shown TPH to be compatible with both glucose and BCD, which are potential excipients both in solid and liquid dosage forms. The presence of these excipients in dosage forms will thus not adversely affect the stability and the therapeutic efficacy of TPH.

Thermal studies on mixtures of benzoic and salicylic acids with cyclodextrins

The thermal behaviour of benzoic and salicylic acids is compared with the behaviour of 1:1 molar ratio physical and kneaded mixtures of these acids with each of three different cyclodextrins (b-, hydroxypropyl-b-, and g-cyclodextrin). Differential scanning calorimetry and thermogravimetry coupled with evolved gas analysis by Fourier transform infrared spectroscopy were used for the thermal studies and X-ray powder diffraction and infrared spectroscopy provided complementary information. Thermal studies of benzoic acid with the cyclodextrins showed significant interactions in both physical and kneaded mixtures of benzoic acid/b-cyclodextrin and benzoic acid/hydroxypropyl-b-cyclodextrin. Interactions in the kneaded benzoic acid/g-cyclodextrin mixtures were the most extensive as might be expected for the cyclodextrin with the largest molecular cavity. The results for the salicylic acid/b-cyclodextrin and salicylic acid/hydroxypropyl-b-cyclodextrin mixtures were similar to those for benzoic acid/b-cyclodextrin and benzoic acid/hydroxypropyl-b-cyclodextrin. Again, the kneaded salicylic acid/g-cyclodextrin mixture showed the most interaction.

Decomposition of solids accompanied by melting--Bawn kinetics.

The book Chemistry of the Solid State, edited by W.E. Garner more than 50 years ago, contained a chapter (Chapter 10) by C.E.H. Bawn which dealt with the kinetics of the thermal decompositions of solids that are accompanied by some melting. Rate equations were derived and this model has become known as the Bawn model or as Bawn kinetics. This kinetic model has proved particularly useful in pharmaceutical stability studies. The isothermal curves of extent of decomposition, alpha, against time for this model are sigmoidal and the problems of distinguishing this model from other sigmoidal models (Prout-Tompkins, Avrami-Erofeev) have been examined. Under programmed temperature conditions, distinguishability becomes even more difficult.

Binary Systems of Nifedipine And Various Cyclodextrins in The Solid State. Thermal, FTIR, XRD studies

Nifedipine complexes with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), randomly methylated-β-cyclodextrin (RM-β-CD) and heptakis(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) have been prepared by both kneading and heating methods and their behaviour studied by differential scanning calorimetry (DSC), diffuse reflectance mid-infrared spectroscopy (FTIR) and X-ray diffractometry (XRD). DSC revealed the nifedipine melting endotherm with onset at approximately 171°C for the kneaded mixtures with β-CD, γ-CD and 2HP-β-CD, thus confirming the presence of nifedipine in the crystalline state, while some decrease in crystallinity was observed in the DM-β-CD kneaded mixture. With RM-β-CD, however, broadening and shifting of the nifedipine endotherm and reduction in its intensity suggested that the kneading could have produced an amorphous inclusion complex. These differing extents of interaction of nifedipine with the cyclodextrins were confirmed by FTIR and XRD studies.

Modelling the thermal behaviour of carboxylic acid derivatives with cylcodextrins in the solid-state

The application of classical QSAR and molecular modelling to the inclusion complexation of natural and modified cyclodextrins (CDs) with carboxylic acid derivatives as guest molecules was examined. Information was available on the thermal behaviour, in the solid-state of benzoic acid (BA), salicylic acid (SA), and various substituted aminosalicylic acids (3-aminosalicylic acid, 3-ASA, 4-aminosalicylic acid, 4-ASA and 5-aminosalicylic acid, 5-ASA), as well as on the thermal behaviour of 1:1 molar ratio physical and kneaded mixtures of these acids with each of three different cyclodextrins, β-, (BCD) 2-hydroxypropyl-β-, (HPBCD) and γ-cyclodextrin (GCD). The thermal behaviour of the binary (1:1 stoichiometry) mixtures was modelled using stepwise multiple regression (SMR). Two models for the prediction of the percentage mass loss and enthalpy of dehydration of the physical mixtures were established with correlation coefficients (r) of 0.79 and 0.92, respectively. Decreased correlation in the thermal behaviour of kneaded mixtures indicated significant interaction and possible formation of inclusion complexes.

Thermal studies on mixtures of aminosalicylic acids with cyclodextrins

The thermal behaviour of the aminosalicylic acids is compared with the behaviour of their 1:1 molar ratio physical and kneaded mixtures with each of three different cyclodextrins (b-, hydroxypropyl-b-, and g-cyclodextrin), using differential scanning calorimetry and thermogravimetry coupled with evolved gas analysis by Fourier transform infrared spectroscopy. X-ray powder diffraction and infrared spectroscopy provided complementary information. Comparison of the effects of the different cyclodextrins on the behaviour of the individual aminosalicylic acid isomers shows that hydroxypropyl-b-cyclodextrin has the greatest interaction with 3-aminosalicylic acid and 5-aminosalicylic acid, followed by g-cyclodextrin, while b-cyclodextrin generally shows the least interaction. For 4-aminosalicylic acid, the effect of g-cyclodextrin seems to be more marked than for 3-aminosalicylic acid and 5-aminosalicylic acid.

Thermal studies on the sodium salts of aminosalicylic acids

The effect on the stability of the isomers of aminosalicylic acid of formation of their sodium salts has been studied by use of differential scanning calorimetry and thermogravimetry, coupled with evolved gas analysis by Fourier transform infrared spectroscopy. X-ray powder diffraction and infrared spectroscopy provided complementary information. The DSC curves for the sodium salts of all of the isomers showed complex dehydration/decomposition endotherms. From the initial mass losses of the TG curves, the amounts of water per mole of salt were estimated as 0.5, 2.4 and 1.4 moles for the sodium salts of 3-aminosalicylic acid, 4-aminosalicylic acid and 5-aminosalicylic acid, respectively. TG-FTIR results for the sodium salt of 3-aminosalicylic acid showed the evolution of carbon dioxide in three stages: below 150°C, between 200 and 300°C and continuous formation up to 500°C. This behaviour differs from that of 3-aminosalicylic acid itself, which forms CO2 between 225 and 290°C. For the sodium salt of 4-aminosalicylic acid, the formation of carbon dioxide starts from 250°C and is still being formed at about 650°C. 4-aminosalicylic acid decarboxylates above 150°C. 5-aminosalicylic acid and its sodium salt showed no evolution of carbon dioxide below 600°C.

Thermoanalytical methods applied to medicine

Thermoanalytical methods have found increasing application in medicine due to the improved sensitivity and usability of the available instrumentation. Studies have identified important findings applied to medicine, including information on the thermal properties of the skin and the effect of insertion into body cavities of implants and prosthetics. These studies have explored the thermal stability of various materials to provide insight into drug penetration in order to design drug delivery systems, which are not only safe but capable of delivering improved and predictable therapeutic outcomes for patients. Differential scanning calorimetry (DSC) has also been applied to the study of disease states such as diabetes, where changes in the collagen structure of the skin which may lead to long-term complications in these patients, can be detected. Although these results may at this stage not have significant clinical implications, they do provide medical researchers with a starting point for future investigations. The application of these techniques has been further extended to examinations of body systems and other disease states. The key for the future will be the ability of these techniques not only to provide information on alterations in these biological systems, but also to determine whether these alterations are clinically relevant.