Monitoring Polymorphic Phase Transitions in Flufenamic Acid Amorphous Solid Dispersions Using Hyphenated X-ray Diffraction-Differential Scanning Calorimetry.

Flufenamic acid (FFA) is a highly polymorphic drug molecule with nine crystal structures reported in the Cambridge Structural Database. This study explores the use of synchrotron X-ray powder diffraction combined with differential scanning calorimetry to study crystallization and polymorphic phase transitions upon heating FFA-polymer amorphous solid dispersions (ASDs). Ethyl cellulose (EC, 4 cp) and hydroxypropylmethylcellulose (HPMC) grades with different viscosities and substitution patterns were used to prepare dispersions with FFA at 5:1, 2:1, 1:1, and 1:5 w/w drug/polymer ratios by quench cooling. We employed a 6 cp HPMC 2910 material and two HPMC 2208 samples at 4000 and 100 000 cp. Hyphenated X-ray diffraction (XRD)-differential scanning calorimetry (DSC) studies show that the 6 and 100 000 cp HPMCs and 4 cp EC polymers can stabilize FFA form IV by inhibiting the transition to form I during heating. It appears that the polymers stabilize FFA in both amorphous and metastable forms via a combination of intermolecular interactions and viscosity effects. Increasing the polymer content of the ASD also inhibits polymorphic transitions, with drug/polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. The comparison of FFA ASDs prepared with different samples of HPMCs and ECs suggests that the chemical substitution of the polymer (HPMC 2208 has 19-24% methoxy groups and 4-12% hydroxypropyl groups, while HPMC 2910 has 28-30% methoxy groups and 7-12% hydroxypropyl groups) plays a more significant role in directing polymorphic transitions than the viscosity. A previously unreported polymorph of FFA was also noted during heating but its structure could not be determined.

Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals.

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.

[Effect of 0.004% travoprost and 2% carteolol on intraocular pressure in patients with ocular hypertension after laser peripheral iridotomy or trabeculectomy in primary angle-closure glaucoma].

OBJECTIVE: To compare the intraocular pressure (IOP) lowering effect of 0.004% travoprost and 2% carteolol in patients with ocular hypertension (OHT) after laser peripheral iridotomy (LPI) or trabeculectomy in primary angle-closure glaucoma (PACG). METHODS: Clinical case control trial. 52 consecutive PACG patients (52 eyes) with IOP > 21 mm Hg (1 mm Hg = 0.133 kPa) after LPI or trabeculectomy were enrolled. 24 patients received topical application of 0.004% travoprost (once daily) and 28 received 2% carteolol (twice daily). IOP lowering effect of travoprost and carteolol before and after treatment was measured by Goldmann tonometer and compared using t-test. The relationship of IOP lowering effect and the degree of angle open was performed by gonioscope and analyzed using Spearman rank correlation. RESULTS: Compared with pre-treatment, the IOP was significantly reduced in 24 patients (24 eyes) in 0.004% travoprost group [pre-treatment: (24.67 ± 3.08) mm Hg, post-treatment: (18.58 ± 2.71) mm Hg; t = 6.600, P < 0.05], while significantly reduced in 28 patients (28 eyes) received 2% carteolol [pre-treatment: (23.57 ± 1.60) mm Hg, post-treatment: (19.57 ± 1.60) mm Hg; t = 5.130, P < 0.05]. 0.004% travoprost group is more significant in both quantity and percentage of IOP lowering than 2% carteolol (t = 2.533, 2.532; P < 0.05). There was no correlation between the IOP lowering effect and the degree of angle open in both groups (0.004% travoprost r = 0.145, 0.009; P > 0.05; 2% carteolol r = 0.090, 0.183, P > 0.05). CONCLUSIONS: Both of 0.004% travoprost and 2% carteolol reduce IOP in patients with OHT after LPI or trabeculectomy in PACG. 0.004% travoprost is more effective than 2% carteolol in IOP lowering. However, the decrease of IOP is not acted through the alteration of anterior chamber angle in both study groups.

Polymorphic transitions in flufenamic acid-trehalose composites.

The combination of poorly-soluble drugs with small molecule co-formers to generate amorphous solid dispersions (ASDs) has great potential to improve dissolution rate and kinetic solubility, and thus increase the bioavailability of these active ingredients. However, such ASDs are known to be unstable and to crystallise upon storage or heating. In this work, we explore the crystallisation of flufenamic acid (FFA) from ASDs prepared with trehalose. FFA-trehalose mixtures were prepared at a range of w/w composition ratios, heated to melting and crash cooled to form ASDs. They were then subject to a further heat/cool cycle, which was monitored by simultaneous differential scanning calorimetry - X-ray diffraction to observe the phase changes occurring. These varied with the composition of the blend. Upon short-term storage, formulations with low trehalose contents (FFA:trehalose 5:1 w/w) recrystallised into form I FFA, while higher trehalose contents crystallised to FFA form IV. When heated, all FFA trehalose combinations ultimately recrystallised into form I before melting. Upon a second cooling cycle, systems with low trehalose content (FFA:trehalose 5:1 w/w) recrystallised into form IV, while higher trehalose contents led to FFA form I. It is thus clear that even with a single excipient it is possible to control the crystallisation pathway through judicious choice of the formulation parameters.

[A novel mutation in the myocilin gene identified in a Chinese primary open angle glaucoma family].

OBJECTIVE: To determine the possible myocilin molecular genetic defect underlying POAG in China and to identify the pathogenic mutation causing the disease. METHODS: The majority of 1 branch of a large Chinese POAG family were personally examined by two senior ophthalmologists. The diagnoses were made by both doctors according to the signs of elevated intraocular pressure, glaucomatous optic neuropathy and glaucomatous visual field defect. All coding sequences of the myocilin gene plus the flanking sites were amplified by polymerase chain reaction (PCR) using genomic DNA from all examined family members followed by sequencing of the PCR products. One hundred normal control subjects were screened by single strand confirmational polymorphism analysis for the mutation. RESULTS: This Chinese pedigree exhibited autosomal dominant mode of inheritance. The onset age ranged from 26 to 59 years. A novel disease-causing missense mutation T455K in the third exon of the myocilin gene was identified in all affected family members, all glaucoma suspects and 4 individuals who have not shown apparently signs of glaucoma. None of the subjects without the mutation had glaucoma. Affected individuals with the T455K mutation showed variable onset between 26 and 59 years of age. Filtering surgery was performed on all of 7 affected family members. The T455K mutation in myocilin gene was not found in the normal controls. A previously reported polymorphism IVS2+35(A to G)was detected in 4 individuals. CONCLUSION: The novel myocilin sequence alteration T455K that is highly associated with the development of glaucoma and locates in a very conserved residue is proven to be a disease-causing missence mutation. All affected individuals and all POAG suspects in this family are identified to have this mutation. The mutation in this family is associated with a phenotype characterized by mix-onset open angle glaucoma and associated with a high penetrance. It is important for the mutation screening and periodical checkups of presymptomatic individuals belonging to the family of a POAG patient with T455K mutation.