Applications of modulated differential scanning calorimetry in preformulation studies.

Characterization of the thermal properties of active pharmaceutical ingredients is critical in the selection of appropriate physical forms for development and defining proper manufacturing, handling and storage conditions of those chemical entities. Modulated differential scanning calorimetry (MDSC) has proven to be an effective tool in the thorough characterization of thermal behavior of compounds in preformulation studies. Selected applications of MDSC for various preclinical compounds are presented, thereby demonstrating the utility of this analytical method in the determination of glass transitions, characterization of desolvation and degradation processes as well as in the study of polymorphic transformations and crystallizations.

The interaction of charged and uncharged drugs with neutral (HP-beta-CD) and anionically charged (SBE7-beta-CD) beta-cyclodextrins.

PURPOSE: The objective of this work was to determine the role that charge might play in the interaction of charged and uncharged drugs with neutral (2-hydroxypropyl-beta-cyclodextrin, HP-beta-CD) and anionically charged (SBE7-beta-CD) modified beta-cyclodextrins. SBE7-beta-CD is a sulfobutyl ether, sodium salt, derivative variably substituted on the 2-, 3- and the 6-positions of beta-cyclodextrin. The number seven refers to the average degree of substitution. METHODS: The binding of the acidic drugs, indomethacin, naproxen and warfarin and the basic drugs, papaverine, thiabendazole, miconazole and cinnarizine with the two cyclodextrins was determined at 25 degrees C as a function of pH and cyclodextrin concentration by the phase-solubility method. RESULTS: Except for miconazole and cinnarizine (Ap-type diagrams), all other materials studied displayed AL-type diagrams. By comparing the binding constants of both the charged and uncharged forms of the same drugs to both HP-beta-CD and SBE7-beta-CD, the following conclusions could be drawn. The binding constants for the neutral forms of the drugs were always greater with SBE7-beta-CD than with HP-beta-CD. For the anionic agents, the binding constants between SBE7-beta-CD and HP-beta-CD were similar while the binding constants for the cationic agents with SBE7-beta-CD were superior to those of HP-beta-CD, especially when compared with the neutral form of the same drug. CONCLUSIONS: A clear charge effect on complexation, attraction in the case of cationic drugs and perhaps inhibition in the case of anionic drugs, was seen with the SBE7-beta-CD.

Chloramine-T in radiolabeling techniques. II. A nondestructive method for radiolabeling biomolecules by halogenation.

Chloramine-T (CAT) is commonly used in the radiolabeling of bioactive molecules by halogenation. CAT may be used either as a solution or in an immobilized form (Iodobeads) to release radioactive elemental iodine or other halogens by oxidation of their salts. CAT has a very high chlorine potential, and it causes oxidative damage to sensitive substrate molecules, such as peptides and proteins. In some cases, the substrates are completely destroyed. To reduce the chlorine potential of CAT, morpholine was mixed with CAT prior to exposure to the substrates. This formed N-chloromorpholine, in situ, which readily reacted with KI to form I2. The kinetics of the formation of N-chloromorpholine from CAT and morpholine were studied spectrophotometrically by following the disappearance of CAT at 250 nm. The reaction was found to be rapid at all pH's from 5 to 11. 1-Aminocyclohexanecarboxylic acid (a model amino acid) decomposed rapidly in the presence of CAT, but there was no decomposition in the presence of N-chloromorpholine. N-Chloromorpholine was compared to CAT solution and Iodobeads for the iodination of L-tyrosine. The formation of mono- and diiodotyrosine were followed by HPLC. On an equimolar basis (0.55 microM), N-chloromorpholine produced a much greater yield of the mono- and diiodinated tyrosine than Iodobeads. Furthermore, decomposition products were observed when tyrosine was exposed to Iodobeads for 15 min. When a CAT solution was used at a higher concentration (5.5 microM), a substantial amount of decomposition occurred, and the yields of the two iodinated species were very small.(ABSTRACT TRUNCATED AT 250 WORDS)