Tuning solubility and stability of hydrochlorothiazide co-crystals

Hydrochlorothiazide (HCT), C7H8ClN3O4S2, is a diuretic BCS (Biopharmaceutics Classification System) class IV drug which has primary and secondary sulfonamide groups. To modify the aqueous solubility of the drug, co-crystals with biologically safe co-formers were screened. Multi-component molecular crystals of HCT were prepared with nicotinic acid, nicotinamide, succinamide, p-aminobenzoic acid, resorcinol and pyrogallol using liquid-assisted grinding. The co-crystals were characterized by FT-IR spectroscopy, powder X-ray diffraction (PXRD) and differential scanning calorimetry. Single crystal structures were obtained for four of them. The N-H center dot center dot center dot O sulfonamide catemer synthons found in the stable polymorph of pure HCT are replaced in the co-crystals by drug-co-former heterosynthons. Isostructural co-crystals with nicotinic acid and nicotinamide are devoid of the common sulfonamide dimer/catemer synthons. Solubility and stability experiments were carried out for the co-crystals in water (neutral pH) under ambient conditions. Among the six binary systems, the co-crystal with p-aminobenzoic acid showed a sixfold increase in solubility compared with pure HCT, and stability up to 24 h in an aqueous medium. The co-crystals with nicotinamide, resorcinol and pyrogallol showed only a 1.5-2-fold increase in solubility and transformed to HCT within 1 h of the dissolution experiment. An inverse correlation is observed between the melting points of the co-crystals and their solubilities

Polymorphism in secondary benzene sulfonamides

The role of about 20 different solvents in the crystallization of polymorphs for 13 N-phenyl benzene sulfonamides was studied. Five compounds (1, 2, 3, 7, and 11) are dimorphic, and one is trimorphic (6). All the crystalline solids were characterized by powder and single crystal X-ray diffraction, thermal analysis, hot stage microscopy, and IR and Raman spectroscopy. The phase transition from a metastable form to the stable form was examined visually for two compounds (1, 11) on a HSM and confirmed by differential scanning calorimetry and X-ray diffraction. The N-H···O hydrogen bond catemer (chain) and dimer (cyclic) motifs of the sulfonamide group were analyzed as the main difference between polymorphs of 1, 3, and 6. Weaker C-H···O interactions differentiate the molecular packing of other polymorphic systems. Accordingly, these crystal structures are referred to as synthon polymorphs. The occurrence of N-H···O catemer and dimer synthon in secondary sulfonamides is compared with crystal structures in the Cambridge database. The nearly equal probability of the dimer and catemer motifs for secondary sulfonamides (~19%) is attributed to the possibility of making the catemer synthon via both anti and syn oxygen atoms of the SO2NH group, with the former acceptor being preferred in two-thirds of the cases

Polymorphism in isomeric dihydroxybenzoic acids

Multifunctional molecules are capable of assembling via different supramolecular synthons, or hydrogen bond motifs, between the same or different functional groups, leading to the possibility of polymorphism. We have employed sublimation and melt crystallization to generate two new crystalline polymorphs of 3,5-dihydroxybenzoic acid (DHBA), and a second form for 2,3-dihydroxybenzoic acid and 3,4-dihydroxybenzoic acid each. Since hydroxybenzoic acids tend to give solvate/hydrate crystal structures by solution crystallization, solvent-free methods are necessary to obtain single crystals of unsolvated forms. In addition to guest-free polymorphs, a new hydrate polymorph of 3,4-dihydroxybenzoic acid was crystallized from cold water. Polymorphs of dihydroxybenzoic acids differ in the number of symmetry-independent molecules (Z'), the nature of the hydrogen bond synthon, the molecular packing, and the unit cell parameters. Structural and thermal characterization of polymorphic phases shows that the commercial material matches with the high Z' phase for 2,3-DHBA, 3,5-DHBA, and 3,4-DHBA hydrate even though a low Z' crystal structure is known in each case. Solventless crystallization conditions at high temperature are a practical method to generate new guest-free polymorphs and high Z' crystal structures for high affinity functional group compounds

Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt

Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM–INA cocrystal and a binary adduct ACM–PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM–PAM and ACM–CPR, and the piperazine salt ACM–PPZ were solved from high-resolution powder X-ray diffraction data. The ACM–INA cocrystal is sustained by the acid...pyridine heterosynthon and N—H...O catemer hydrogen bonds involving the amide group. The acid...amide heterosynthon is present in the ACM–PAM cocrystal, while ACM–CPR contains carboxamide dimers of caprolactam along with acid–carbonyl (ACM) hydrogen bonds. The cocrystals ACM–INA, ACM–PAM and ACM–CPR are three-dimensional isostructural. The carboxyl...carboxyl synthon in ACM–PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24 h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM–PPZ salt and ACM–nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM–PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug

Obtaining Synthon Modularity in Ternary Cocrystals with Hydrogen Bonds and Halogen Bonds

Design of ternary cocrystals based on synthon modularity is described. The strategy is based on the idea of extending synthon modularity in binary cocrystals of 4-hydroxybenzamide:dicarboxylic acids and 4-bromobenzamide:dicarboxylic acids. If a system contains an amide group along with other functional groups, one of which is a carboxylic acid group, the amide associates preferentially with the carboxylic acid group to form an acidamide heterosynthon. If the amide and the acid groups are in different molecules, a higher multicomponent molecular crystal is obtained. This is a stable pattern that can be used to increase the number of components from two to three in a multicomponent system. Accordingly, noncovalent interactions are controlled in the design of ternary cocrystals in a more predictable manner. If a single component crystal with the amideamide dimer is considered, modularity is retained even after formation of a binary cocrystal with acidamide dimers. Similarly, when third component halogen atom containing molecules are introduced into these binary cocrystals, modularity is still retained. Here, we use acidamide and Br/I center dot center dot center dot O2N supramolecular synthons to obtain modularity in nine ternary cocrystals. The acidamide heterosynthon is robust to all the nine cocrystals. Heterosynthons may assist ternary cocrystal formation when there is a high solubility difference between the coformers. For a successful crystal engineering strategy for ternary cocrystals, one must consider the synthon itself and factors like shape and size of the component molecules, as well as the solubilities of the compounds

Role of Upbringing and Educational aspects in the Preferences and Aspirations of Individuals from Socially Excluded Areas

Dissertational thesis is about children from socially excluded areas particularly their aspirations regarding their education and their preferred choice of subjects. We use the traits of their environment to address and specify terms, which we chose to describe the peculiarities in education and the principles of socialization of these children. Further, we define the relationship of the family to school. The empirical part of this thesis analyzes in detail the methods we used during our research. The research is based on both quantitative analysis using questioners and qualitative in- depth interviewing methods. The goal of our research is to find out whether students from socially excluded areas have the same attitude toward their future as children from prevalent areas. Whether these students have the same subject preferences and ideas about their future employment. We discuss the findings of this research further in order to apply them in a real educational environment. This research found out that children from excluded areas have very similar ideas about their future employment. They also prefer similar subjects compared to students from prevalent areas. KEYWORDS: Socially excluded area, Roma child, socialization, family, education, vocational aspiratio

Holding company as matter of fact (selected issues)

Holding company as matter of fact In the 19th century the concept of artificial legal persons as independent legal entities separate from their shareholders was created. The joining of companies into corporate groups is in contradiction with the abovementioned concept. Nevertheless, corporate groups are a reality and every legislator had to deal with this issue and create sufficient legislation, considering the protection of minority shareholders on the one hand and the possibilities of the evolution of corporate groups on the other hand. Current Czech legislation regarding corporate groups is more than 10 years old and yet there are still contradictions in the interpretation of the basic provisions of the law of corporate groups amongst experts. My thesis is divided into two parts: the first part consists of the interpretation of the basic provisions of the Commercial Code regarding corporate groups. I used all the basic methods of interpretation, especially the comparison of different expert opinions to provide complex and clear interpretation. The goal of the first part was to point out the abovementioned contradictions and offer my own point of view to readers. In the second part of the thesis, I focused on the option of the holding company to force the controlled company to enter into an..

Temozolomide Cocrystals with Carboxamide Coformers

Temozolomide (TMZ) is an antitumor prodrug of broad spectrum antineoplastic activity. TMZ is stable in acidic medium (pH < 4) but starts to decompose at alkaline pH (>7). In continuation of our efforts to design stable cocrystals of TMZ with partners such as organic acids (p<i>K</i>_a 2–5) and a salt dihydrate with hydrochloric acid, we report herein TMZ cocrystals with amide coformers, e.g., isonicotinamide, nicotinamide, pyrazinamide, <i>p</i>-hydroxybenzamide, saccharin, and caffeine. TMZ exhibits polymorphs in the <i>p</i>-hydroxybenzamide cocrystal (synthon polymorphism). The occurrence of the stable conformation A of temozolomide and metastable conformation B (energy difference 1.44 kcal mol^–1) in amide cocrystals is compared with the overall statistics in temozolomide cocrystal structures and polymorphs. The novel cocrystals were characterized by spectroscopic, X-ray diffraction, and thermal methods

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H center dot center dot center dot O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug