Tuning the cocrystal yield in matrix-assisted cocrystallisation via hot melt extrusion: A case of theophylline-nicotinamide cocrystal.

Polymer-assisted cocrystallisation via hot melt extrusion (HME) facilitates the cocrystallisation process and increases cocrystal yield compared with the HME of neat cocrystal components. This makes it an attractive method for the single-step continuous synthesis of pharmaceutical cocrystals. The aim of this study is to understand the effect of semicrystalline (Poloxamer P407, PXM) or amorphous (Soluplus®, SOL) polymers on the cocrystallisation of model theophylline-nicotinamide (TP:NA, 1:1) cocrystal with significantly different melting temperatures of API (TP, m.p. = 271.4 °C) and coformer (NA, m.p. = 128.7 °C) in neat and matrix-assisted cocrystallisation via HME. Compared with the processing of neat cocrystal components, the addition of PXM led to formulation of TP:NA cocrystal embedded in the polymer matrix and increased the cocrystal formation efficiency. On the other hand, the co-processing of cocrystal components with SOL resulted in the formation of cocrystal embedded in the amorphous polymer matrix or in the partially amorphous TP:NA/SOL composites. The one-step formulation of API:coformer mixtures with polymers using HME may result in phase changes or the formation of amorphous solid dispersions, which highlights the importance of matrix selection and phase control of the final product.

Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing - State of the art.

Use of hot melt extrusion (HME) as continuous manufacturing process in the cocrystal synthesis is of increasing interest from both industrial and academic perspective and it is seen as a newly developing branch of mechanochemistry with possible broad application in single step synthesis and formulation of pharmaceutical cocrystals. Furthermore, one-step formulation of pharmaceutical products results in combined processing of pharmaceutical cocrystal mixtures with polymers using HME, which may result in phase change or formation of amorphous solid dispersions during the material processing. The manuscript aims at providing selection guidelines and understanding of processing parameters and instrumental setup of importance to design the HME process for cocrystal synthesis. Furthermore, importance of stoichiometry control of the final product and the matrix selection criteria in simultaneous synthesis and formulation of pharmaceutical cocrystals via HME are provided. The first part of this review, introduce mechanochemical methods of cocrystals synthesis along brief explanation of the possible molecular mechanisms of cocrystal synthesis via mechanochemical approach. Subsequently, the critical process parameters i.e. temperature, screw speed, screw configuration or material feed rate of importance in successful synthesis of high quality product are described followed by literature examples of the processing of neat cocrystal compounds or matrix assisted cocrystallisation.

The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal.

Solid-state synthesis of pharmaceutical cocrystals is of contemporary interest as it offers an efficient way to modify the physicochemical properties of Active Pharmaceutical Ingredient (API) including its melting point, solubility, compressibility or physical stability, without compromising its structural integrity and bioactivity. Therefore, research of novel and emerging techniques for solvent-free, continuous and scalable methods for cocrystal formation is of paramount importance for further industrial development. In this work we form a basis for knowledge-based synthesis and formulation of model pharmaceutical cocrystal (flufenamic acid, FFA: nicotinamide, NA; 1:1) via matrix-assisted cocrystallisation (MAC) using Hot Melt Extrusion (HME). Five different polymers frequently used in pharmaceutical drug delivery: Poloxamer P407 (PXM), PEG-PVA copolymer, Soluplus® (SOL), PVPVA64 and HPMCAS with different structural features and physicochemical properties were investigated as functional matrices for FFA:NA cocrystal synthesis via HME. Significant decrease of the torque value during MAC process was observed for all investigated polymers as compared to extrusion of neat FFA:NA cocrystal. The FFA:NA cocrystal encapsulated in the polymer matrix was successfully formed using semicrystalline PXM and PEG-PVA polymers at all investigated FFA:NA/polymer ratios. The use of amorphous polymers (SOL, PVPVA64, HPMCAS) as a cocrystallisation matrix resulted in formation of FFA:NA cocrystal embedded in an amorphous FFA:NA/polymer matrix (at polymer contents of 10 and 20 wt.%) or FFA:NA/polymer amorphous composites at SOL and PVPVA64 content of 30 wt.%. Furthermore, the significant increase of FFA dissolution was observed for FFA:NA cocrystal encapsulated in PXM and PEG-PVA matrices as compared to neat FFA form I. FFA form III and FFA:NA cocrystal. The presented work enables for the first time knowledge-based approach for simultaneous synthesis and formulation of pharmaceutical cocrystals via Hot Melt Extrusion a solvent-free, scalable and continuous process.

Thermal stability and decompositions kinetics under non-isothermal conditions of imatinib mesylate α form.

The thermal decomposition and kinetic parameters of synthetized imatinib mesylate α form α form were determined by thermogravimetry (TGA/DTG) under non-isothermal conditions. The experiments were performed at a 25-940°C temperature range at five different heating rates: 2.5Kmin(-1), 5Kmin(-1), 10Kmin(-1), 15Kmin(-1) and 20Kmin(-1) per minute in a nitrogen atmosphere. Imatinib mesylate α form presents one-step mass loss during the degradation process. The thermal stability of the examined material, the melting temperature (Tonset=220.6°C) and ΔH fusion=-95.74Jg(-1) at a heating rate of 10°Cmin(-1) was established. The values of activation energies have been estimated using Kissinger, Flynn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) methods.

Physicochemical characterization and dissolution studies of acyclovir solid dispersions with Pluronic F127 prepared by the kneading method.

The dissolution rate of anhydrous acyclovir was improved by the preparation of physical mixtures and solid dispersions with the non-ionic polymer Pluronic F127 using the kneading method at different drug-to-polymer ratios. The obtained physical mixtures and solid dispersions were examined in terms of drug content and possible physical and chemical interactions between the drug and polymer using FTIR spectral studies, differential scanning calorimetry and powder X-ray diffraction analysis. The dissolution rate of acyclovir was determined using the rotating disk method. It was found that the minimal content of the polymer within the mixtures needed to increase the dissolution rate of the drug was 50 %.

FORMULATION AND EVALUATION OF MICROSPHERES CONTAINING LOSARTAN POTASSIUM BY SPRAY-DRYING TECHNIQUE.

Despite numerous applications of microspheres, few works devoted to the preparation of microspheres containing cardiac medications have been published. This study presents the potential of receiving microspheres containing losartan potassium, based on a matrix containing Eudragit L30D55. The study focuses on the possibilities of controlled release of losartan potassium from microspheres in order to reduce the dosage frequency, and also provides information on the effect of the addition of excipients to the quality of the microspheres. Microspheres are monolithic, porous or smooth microparticles ranging from 1 to 500 microns in size. For the preparation of microspheres containing losartan potassium, the spray-drying method was used. The performed study confirmed that the spray-drying technology used to obtain microspheres meets the criteria of size and morphology of the microparticles. The assessment of the kinetics of losartan potassium release from the examined microspheres demonstrated that the release profile followed the first- and/or zero-order kinetics. The use of spray-drying techniques as well as Eudragit L30D55 polymer matrix to obtain the microspheres containing losartan potassium makes it possible to obtain a product with the required particle morphology and particle size ensuring the release of the active substance up to 12 h.

THERMOSENSITIVE MICROGELS OF POLY-N-ISOPROPYLACRYLAMIDE FOR DRUG CARRIERS--PRACTICAL APPROACH TO SYNTHESIS.

The aim of the work is to present the main actual information on the preparation of polymers, derivatives of N-isopropylacrylamide, formed into microgels. The most often used comonomers, crosslinkers, and initiator systems are gathered herein. The known methods of emulsion polymerization and precipitation polymerization are also described, including the application of the surfactants, as well as the surfactant free emul- sion polymerization. Finally, the procedures of lab-scale production of microgel were evaluated in the paper, with special intact on the thermosensitive N-isopropylacrylamide derivatives for application in biomedical field.

The Conductivity and pH Values of Dispersions of Nanospheres for Targeted Drug Delivery in the Course of Forced Equilibrium Dialysis.

BACKGROUND: In the available literature, the problem of pH and conductivity in FED is evaluated separately, and limited mainly to the final purity of the synthesized polymer. In this study data from conductivity and pH measurements were evaluated in the context of the structure of the macromolecule. OBJECTIVES: The aim of the study was to evaluate the conductivity and pH of dispersions of nanospheres synthesized with the use of N-isopropyl acrylamide (NIPA) as the main monomer, N,N'-methylenebisacrylamide (MBA) as the cross-linker and acrylic acid (AcA) as the anionic comonomer during the purification of dispersions via forced equilibrium dialysis (FED). MATERIAL AND METHODS: Six batches of nanospheres were obtained in the process of surfactant free precipitation polymerization (SFPP) under inert nitrogen. The conductivity and pH of the dispersions of nanospheres were measured at the beginning of FED and after finishing that process. The conductivity in the systems being studied decreased significantly in the process of FED. The initial values of conductivity ranged from 736.85±8.13 µS×cm(-1) to 1048.90±67.53 µS×cm(-1) After 10 days, when the systems being assessed gained stability in terms of conductivity level, the values of conductivity were between 4.29±0.01 µS×cm(-1) and 33.56±0.04 µS×cm(-1). The pH values inreased significantly after FED. The resulting pH was between 6.92±0.07 and 8.21±0.07, while the initial values were between 3.42±0.23 µS×cm(-1) and 4.30±0.22 µS×cm(-1). CONCLUSIONS: Conductivity and pH measurements performed during purification via FED provide important information on the composition of the resulting nanospheres, including the functional groups embedded in the structure of the polymer in the course of the synthesis, as well as the purity of the structures. The presence of a cross-linker and acidic comonomer in the poly-N-isopropyl acrylamide (polyNIPA) macromolecule may be confirmed by both the pH and the conductivity measurements.

Synthesis and antibacterial properties of pyrimidine derivatives.

In this study, a series of syntheses was conducted on the pyrimidine system, obtaining bisulfite carboxyl derivatives 4 and hydroxy derivatives 5. In addition, a series of syntheses were carried out as a result of which both alkyl and aromatic amines were obtained. Then, the attempt was made to cyclize these amines in the Mannich reaction to pyrimido[4,5-d]pyrimidines 11, 12. After determination of chemical structure using physicochemical tests, also by means of crystallographic tests, all the newly obtained derivatives underwent microbiological tests on bacterial strains and fungi. The most interesting results of the microbiological tests are included later in the study.

The impact of selected preparations of trace elements - magnesium, potassium, calcium, and zinc on the release of diclofenac sodium from enteric coated tablets and from sustained release capsules.

BACKGROUND: In an aging society, many patients require long-term treatment. This fact is associated clearly with the simultaneous occurrence of lifestyle diseases such as hypertension, diabetes, and even osteoarthritis. Concomitant medications, which are a common practice, pose a major threat of an interaction between these drugs. Very popular now "fast way of life" that makes people have less and less time to prepare well-balanced meals of high nutritional value. The result of this lifestyle is an increased need for supplementation preparations necessary vitamins and minerals. Given the wide availability of dietary supplements (shops, kiosks, petrol stations) raises the question about the possibility of an interaction between the uncontrolled intake of dietary supplements and medications received in the most common diseases of civilization. OBJECTIVES: The aim of this study was to investigate the effect of the most important minerals (magnesium, potassium, calcium, zinc) contained in the popular nutritional supplements, the release also often used as an anti-pain, anti-inflammatory, diclofenac sodium from the different formulations. RESULTS: Among the many as sodium diclofenac selected two most common: film-coated tablets and sustained release capsules. The study showed a significant effect of minerals on the release of diclofenac sodium and differences that impact, depending on the test form of the drug.

Stability evaluation of thermosensitive drug carrier systems based on Pluronic F-127 polymer.

The aim of this study was to evaluate the stability of thermosensitive systems based on Pluronic F-127 polymer, in aspects of their possible application in novel drug technology. A formulation was prepared without any active ingredient, consisting of 16% (w/w) of polymer dissolved in aqueous medium. Such preparation was autoclaved and then subjected to 3-month conditioning at elevated (40 degrees) and reduced (5 degrees C) temperature. Rheological parameters: viscosity, consistency and sol-gel transition characteristics were studied in 1-month interval. The significance of measured changes was evaluated by proper statistical analyses. Significant changes exceeding the established criteria (+/- 10% of every initial value) were observed during the study. Furthermore, total involution of sol-gel transition phenomenon was observed in samples stored at 40 degrees C. Results indicate the lack of stability in tested formulation at both of storage conditions. However, some regularity indicates that the stability at reduced temperature could be confirmed, if only the concentration of polymer and the measurements schedule were slightly modified.

Ophthalmic drug dosage forms: characterisation and research methods.

This paper describes hitherto developed drug forms for topical ocular administration, that is, eye drops, ointments, in situ gels, inserts, multicompartment drug delivery systems, and ophthalmic drug forms with bioadhesive properties. Heretofore, many studies have demonstrated that new and more complex ophthalmic drug forms exhibit advantage over traditional ones and are able to increase the bioavailability of the active substance by, among others, reducing the susceptibility of drug forms to defense mechanisms of the human eye, extending contact time of drug with the cornea, increasing the penetration through the complex anatomical structure of the eye, and providing controlled release of drugs into the eye tissues, which allows reducing the drug application frequency. The rest of the paper describes recommended in vitro and in vivo studies to be performed for various ophthalmic drugs forms in order to assess whether the form is acceptable from the perspective of desired properties and patient's compliance.

[The effect of selected excipients on properties hydrogels on the basis Carbopol 934P]. / Wplyw wybranych substancji pomocniczych na wlasciwosci zeli na bazie Carbopolu 934P.

UNLABELLED: AIM OF THE STUDY. The study on the effect of absorption promotors on the properties of hydrogels prepared from Carbopol 934P basis containing 1% hydrocortisone. MATERIALS: hydrocortysone, Carbopol 934P, propylene glycol-1,2 N,N-dimethylacetamide purified water to P Ph 9th Ed., ethanol 760 g/1, Tween 20. Dynamic viscosity test: was carried out using the Rheotest 2. The values of the shear stress and viscosity were calculated from measurements. Consistency test--TPA test was performed with Exponent Stable Micro Systems texture analyzer. Examination of pharmaceutical availability of hydrocortisone: The process of hydrocortysone release from hydrophilic base was carried out according to the method based on active substance diffusion through a semi-permeable membrane. Concentration of hydrocortysone according to Polish Pharmacopoeia 9th Ed. RESULTS: Rheological studies showed that the process is nonlinear. Tested gels shows thixotropic properties. The tension decreases with the increase in the percentage of excipients. Hardness tests showed that in comparison to the reference gel, pressure force increased in the presence of 1% of the excipients in the gel, and the reduction in the presence of 15% of the excipients. Gels are characterized with greater cohesiveness than the control preparation. The release process of the drug substance proceeds in accordance with first order kinetics. Increasing concentrations of used absorption promotors influenced on increase the number of hydrocortisone released from the hydrogels prepared on the basis of 3% Carbopol 934 F gel. CONCLUSIONS: 1. Tested gels are showing thixotropic propereties and are non-Newtonian systems. 2. The hardness and cohesiveness of the gels increases with increasing concentrations of the excipients. 3. The value of the constant release rate is increases in the presence of ethanol, Tween 20, and DMA.

[Influence of the gelatin-alginate matrixes with calcium lactate in plasma coagulation system after implantation in soft tissues]. / Wplyw matryc zelatynowo-alginianowych z mleczanem wapnia na osoczowy uklad krzepniecia po implantacji w tkanki miekkie.

BACKGROUND: Bioresorbable porous substrates from copolymers have their application in tissue engineering to culture tissues in vitro. The advantage of polymers is the production of thermoplastic elements and their ability to biodegrade in a living body. Gelatin, collagen, alginates are part of dressings used for topical administration of the drug. Research was undertaken to achieve a porous gelatin-alginate matrix which could be used in therapy as among others, a carrier for a drug. OBJECTIVES: Evaluation of the impact of modified gelatin-alginate matrix on activation of plasma coagulation in vivo. MATERIAL AND METHODS: Gelatin-alginate matrix cross-linked with calcium ions was implanted in the muscle tissue of a rat. The control group constituted animals not implanted with material, but they passed the operating procedure. Blood samples of plasma coagulation test and control group were collected after 1, 2, 3, 5, 7, 10, 14 days of the procedure. RESULTS: Prolongation of APTT and shortening of PT and TT with the unchanged values of fibrinogen and the count of platelet cells was observed till the 5th day on the basis of the obtained results. Prolongation of APTT with the unchanged values of the remaining parameters of the coagulation system was observed after 7, 10 and 14 days with unchanged values of PT and TT coagulation. CONCLUSIONS: The matrix gelatin-alginate with calcium ions in the biological environment undergoes biodegradation in soft tissues. This process in the initial period influences the activation of the coagulation within the intrinsic and extrinsic system. From the 5th to 14th day the activation of coagulation was observed only in the intrinsic system.

[Influence of gelatin-alginian matrixes on morphological and functional changes of blood leukocytes]. / Wplyw matryc zelatynowo-alginianowych na zmiany morfologiczne i czynnosciowe leukocytów krwi.

BACKGROUND: Knowledge of the relation of biomaterials and living tissues constitutes necessary information which should be used when composing a set of optimal carriers, e.g. for drugs or preparations supporting blood clotting. OBJECTIVES: This paper presents an assessment of the influence of contact of gelatin-alginian matrixes with blood on leukocyte reactivity: the ability of mononuclear cells (lymphocytes and monocytes) to create a radial segmentation of nuclei--RS (the morphological change), and the ability of leukocytes to phagocytosis of yeast Saccharomyces cerevisiae cells and to produce active oxygen derivatives (functional changes). MATERIAL AND METHODS: After having contact with the matrixes, the test of induced and spontaneous RS, the phagocytic test and nitroblue tetrazolium reduction test for blood leukocytes were performed. RESULTS: The obtained results showed a decrease in the ability of mononuclear cells to form RS and in the ability of granulocytes to reduce nitroblue tetrazolium--NBT, but an increase in their phagocytic activity. CONCLUSIONS: Temporary contact of gelatin-alginian matrixes with blood did not cause any morphological changes in the leukocytes. However, changes of their reactivity were observed.

N-(4-Meth-oxy-phen-yl)-6-methyl-2-phenyl-5-{[4-(tri-fluoro-meth-yl)anilino]meth-yl}pyrimidin-4-amine.

The title compound, C26H23F3N4O, crystallizes with two symmetry-independent mol-ecules in the asymmetric unit, denoted A and B, which differ mainly in the rotation of the meth-oxy-phenyl ring. The -CF3 group of mol-ecule B is disordered by rotation, with the F atoms split over two sets of sites; the occupancy factor for the major component is 0.853 (4). The dihedral angles between the pyrimidine ring and the attached phenyl, meth-oxy-phenyl and tri-fluoro-methyl-phenyl rings are 8.1 (2), 37.5 (2) and 70.7 (2)°, respectively, in mol-ecule A, and 9.3 (2), 5.3 (2) and 79.7 (2)° in mol-ecule B. An intra-molecular N-H⋯N hydrogen bond occurs in each mol-ecule. In the crystal, two crystallographically independent mol-ecules associate into a dimer via a pair of N-H⋯N hydrogen bonds, with a resulting R 2 (2)(12) ring motif and π-π stacking inter-actions [centroid-centroid distance = 3.517 (4) Å] between the pyrimidine rings. For the A mol-ecules, there are inter-molecular C-H⋯O hydrogen bonds between an aryl C atom of meth-oxy-phenyl ring and a meth-oxy O atom of an adjacent mol-ecule. A similar inter-action is lacking in the B mol-ecules.

[Effect of the medium composition on the properties of gels based on sodium carboxymethylcellulose]. / Wplyw skladu podloza na wlasciwosci zeli wykonanych na bazie soli sodowej karboksymetylocelulozy.

BACKGROUND: Sodium carboxymethylcellulose is a hydrogel substrate used in the Drug Formulation Technology to produce skin dressings, dental gels and the ophthalmic drugs. OBJECTIVES: To study the hydrophilic medium composition based on the sodium carboxymethylcellulose and excipients on the properties of hydrogels with 1% hydrocortisone. MATERIAL AND METHODS: Sodium carboxymethylcellulose, hydrocortisone, Tween 20, Ethanol 760 g/l, propylene glycol-1,2, N,N-dimethylacetamide, aqua purificata P Ph 9th. The dynamic viscosity were determined by the method described in a previous publication [9]. The test of the consistence: the hardness and cohesiveness of the hydrogels were tested by TPA test. Hydrocortisone release experiment was performed according to PPh 9th by the paddle apparatus. The amount of drug was determined by spectrophotometry method. RESULTS: Hydrogel dressings show thixotropic properties, they are non-Newtonian fluids. The addition of increasing amounts of excipients reduces the shear stress. Compared to the control formulations, tested hydrogels are more cohesive, have a lower hardness with addition of 1% of Ethanol, Tween 20 and higher in other cases. Pharmaceutical availability of hydrocortisone follows the first order kinetics. Excipients added to the gels are speeding up the process in the presence of DMA, but are extending process with propylene glycol-1,2, Ethanol and Tween 20. CONCLUSIONS: Tested hydrogels in the presence of Ethanol, GP-1,2, DMA, Tween 20 exhibit higher shear stress than the control formulations. Hydrogels based on the Na-carboxymethylcellulose are less hard and more cohesive. The drug release follows the first order kinetics.

In vivo study on the biodistribution of silica particles in the bodies of rats.

BACKGROUND: Biodegradable carrier materials with nontoxic degradation products are very valuable for delivering drugs and biologically active molecules. Many organic systems (such as liposomes, micelles and polymeric nanoparticles) and inorganic systems (metal oxides and silica) have been researched for delivering active substances to organs. Silica seems to be one of the most interesting and promising materials. OBJECTIVES: The aim of this study was to investigate the SiO2 elimination process from rats' organisms and to ascertain the distribution and prospective accumulation sites of the silica particles. MATERIAL AND METHODS: A suspension of silica particles (Ø 150 nm) in 0.9% NaCl solution was introduced into rats' circulatory system. The degradation of these particles over time and their accumulation in the heart, lungs, kidneys and liver were observed. RESULTS: It was found that 36% of the introduced silica particles were excreted with urine after four days. The remaining particles were accumulated in the kidneys and lungs, probably in the lung air sacs and kidney glomerulus. CONCLUSIONS: Silica seems to be promising carrier material. Silica particles dissolve in the rat's body and are eliminated in urine.

Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their application.

In the first part of the article solid dispersions were classified the properties and methods of their preparation were described. This section presents methods of analysis of solid dispersions i.e.: thermoanalytical methods, XRPD, FTIR, microscopic methods, dissolution studies and examples of drug forms where solid dispersions were used.

Solid dispersions in pharmaceutical technology. Part I. Classification and methods to obtain solid dispersions.

There are many methods to increase solubility of a substance. These include, inter alia, preparation of solid dispersions, i.e. eutectic mixtures, solid solutions, glassy solutions and suspensions. When compared to the individual constituents prior to dispersion formation solid dispersion components are better soluble in water. Therefore, solid solutions became one of the most promising ways to modify solubility, ensuring improved bioavailability and consequently therapeutic efficacy of a substance. In this part of the publication solid dispersions were classified and described in regard to their properties and preparation methods, i.e. melting method, melt evaporation and melt extrusion methods, lyophilisation technique, melt agglomeration process as well as SCF technology and electrospinning.