Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.

Direct compression of cellulose and lignin isolated by a new catalytic treatment.

Tablet compression of softwood cellulose and lignin prepared by a new catalytic oxidation and acid precipitation method were investigated and compared with the established pharmaceutical direct compression excipients. Catalytic pretreated softwood cellulose (CPSC) and lignin (CPSL) were isolated from pine wood (Pinus sylvestris). The compaction studies were carried out with an instrumented eccentric tablet machine. The plasticity and elasticity of the materials under compression were evaluated using force-displacement treatment and by determining characteristic plasticity (PF) and elasticity (EF) factors. With all biomaterials studied, the PF under compression decreased exponentially as the compression force increased. The compression force applied in tablet compression did not significantly affect the elasticity of CPSC and microcrystalline cellulose (MCC) while the EF values for softwood lignins increased as compression force increased. CPSL was clearly a less plastically deforming and less compactable material than the two celluloses (CPSC and MCC) and hardwood lignin. CPSL presented deformation and compaction behaviour almost identical to that of lactose monohydrate. In conclusion, the direct tablet compression behaviour of native lignins and celluloses can greatly differ from each other depending on the source and isolation method used.

Ring opening polymerization of rac-lactide by group 4 tetracarbamato complexes: activation, propagation and role of the metal.

A series of group 4 metal tetracarbamates M(O(2)CNR(2))(4) (M = Ti, R = Et, 1a; M = Zr, R = Et, 1b; (i)Pr, 1c; M = Hf, R = Et, 1d; R = (i)Pr, 1e) were studied as catalytic precursors in the solution polymerization of rac-lactide. The titanium complex but not the zirconium and hafnium ones increase the activity by addition of (i)PrOH. The structure of the carbamato ligand markedly influences the molar mass of polymer; the complexes with isopropyl carbamato ligands produced PLA with molar masses up to 94,000 g mol(-1). The main mechanistic aspects of the initial stages of the polymerization reactions were outlined by spectroscopic and computational analyses. In the case of zirconium and hafnium complexes, an interaction between a carbamato ligand and the CH unit of one lactide molecule is established at room temperature. This interaction is followed by the high temperature proton transfer from the lactide to the carbamato O-atom, affording a catalytic active alkoxy complex with release of CO(2) and NHR(2). The polymerization mediated by Ti(O(2)CNEt(2))(4) involves the release of a radical fragment [O(2)CNEt(2)]˙, with consequent generation of a Ti(III) center. The propagating chain is an alcoholate ligand coordinated to a Ti(IV) centre and containing a radical mainly localized at the tail of the chain (DFT, EPR).

Solid-state properties of softwood lignin and cellulose isolated by a new acid precipitation method.

Solid-state and powder properties of softwood lignin and cellulose prepared by a new catalytic oxidation and acid precipitation method were characterized and compared with the commercial softwood and hardwood lignin and cellulose products. Catalytic pre-treated softwood lignin (CPSL) and cellulose (CPSC) were isolated from pine wood (Pinus sylvestris). CPSL with nearly micronized-scale particle size showed excellent powder flow and densification behavior due to the round shape and electrically minimum charged surface characteristics of particles. CPSL and the reference lignin studied were amorphous solids while CPSC exhibited a typical crystal lattice for cellulose I. In conclusion, physicochemical material properties of lignin and cellulose can be modified for biomedical and pharmaceutical applications with the present catalytic oxidation and acid precipitation method.

Sugar end-capped poly-D,L-lactides as excipients in oral sustained release tablets.

Sugar end-capped poly-D,L-lactide (SPDLA) polymers were investigated as a potential release controlling excipient in oral sustained release matrix tablets. The SPDLA polymers were obtained by a catalytic ring-opening polymerization technique using methyl alpha-D-gluco-pyranoside as a multifunctional initiator in the polymerization. Polymers of different molecular weights were synthesized by varying molar ratios of monomer/catalyst. The matrix tablets were prepared by direct compression technique from the binary mixtures of SPDLA and microcrystalline cellulose, and theophylline was used as a model drug. The tablet matrices showed in vitro reproducible drug release profiles with a zero-order or diffusion-based kinetic depending on the SPDLA polymer grade used. Further release from the tablet matrices was dependent on the molecular weight of the SPDLA polymer applied. The drug release was the fastest with the lowest molecular weight SPDLA grade, and the drug release followed zero-order rate. With the higher molecular weight SPDLAs, more prolonged dissolution profiles for the matrix tablets (up to 8-10 h) were obtained. Furthermore, the prolonged drug release was independent of the pH of the dissolution media. In conclusion, SPDLAs are a novel type of drug carrier polymers applicable in oral controlled drug delivery systems.