Synthesis and characterization of alkyl cellulose ω-carboxyesters for amorphous solid dispersion

Poor drug solubility and consequently poor bioavailability are major impediments to new drug innovation, and they limit the performance of many existing drugs. In recent years amorphous solid dispersion (ASD) has emerged as one of the most effective approaches for enhancing drug solution concentration, and thereby bioavailability, including in many marketed drug formulations. Recently efforts have been under way in several laboratories to design new ASD polymers, rather than relying on polymers that are already in FDA-approved formulations, but were not designed as ASD polymers. We describe here the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters, for ASD formulation. We synthesize these polymers by reaction of cellulose alkyl ethers with monoprotected (benzyl ester), monofunctional long chain acid chlorides, followed by protecting group removal using mild hydrogenolysis to form the target alkyl cellulose ω-carboxyalkanoate. These new amphiphilic polymers have high glass transition temperatures (T_g), tunable carboxyl content for controlling release pH and drug-polymer interactions, and certain members of this new group of amphiphilic cellulose ether esters are shown to be successful at forming ASDs with the important model drug ritonavir. These ASDs efficiently release ritonavir at small intestine pH, creating the maximum attainable amorphous solubility (20 μg/mL), and maintaining it for a time period substantially greater than the normal residence time in the absorptive region of the stomach and small intestine. Members of this new class of alkyl cellulose ω-carboxyester amphiphiles show significant potential as ASD polymers for enhancing oral bioavailability of otherwise poorly soluble drugs.     

Thermal characterization of antimicrobial drug ornidazole and its compatibility in a solid pharmaceutical product

The ornidazole drug substance presents melt at approximately 90 °C (∆T = 85–98 °C), which is critical for its use on pharmaceutical manufacturing process. This work aimed the thermal characterization of ornidazole raw-material synthesized by three different manufacturers from India, China, and Italy, using the thermoanalytical techniques of DTA, DSC, and TG, besides the verification of its stability and compatibility as a solid pharmaceutical product by the analysis of its binary mixtures (BM) with excipients and a tablet formulation. The characterization includes the thermal decomposition kinetic investigation by Ozawa model using Arrhenius equation and drug purity determination by Van’t Hoff equation. The DSC purity determination and precision were compared with results from UV–Vis spectrophotometric and liquid chromatography, showing an adequate correlation before being recommended as a general method for purity assay. The drug raw-materials presented similar quality and zero-order kinetic behavior, besides showing differences on thermal stability. The drug presented compatibility with the tested excipients since the BM studied presented melting at the same temperature range as the drug and a decomposition temperature similar to the drug for two of the BM, and at a higher temperature for the others three of the BM evaluated, which presented excipients with higher molecular structure, capable of spatial coating on the small drug molecule promoting a physical interaction pharmaceutical acceptable. The tablet was processed by wet granulation and compressed under normal conditions of pressure and temperature, maintaining the physical properties of solid drug approving the manufacturing process used. In this study, the thermal analysis was used with success as an alternative method to characterize, quantify, and perform a preformulation study.     

Risperidone/Randomly Methylated β-Cyclodextrin Inclusion Complex—Compatibility Study with Pharmaceutical Excipients

Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated β-cyclodextrin (RM-β-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-β-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.     

Enhancement of naringenin solution concentration by solid dispersion in cellulose derivative matrices

Naringenin (Nar) is an important bioactive flavonoid with poor organic solubility and oral bioavailability. It is highly promising for treatment of conditions including diabetes, hyperlipidemia, and hepatitis C infection. Amorphous solid dispersion (ASD) of Nar is an appealing way to enhance its solubility, and carboxylated cellulose esters are attractive polymers for this purpose because of their ability to stabilize drugs against crystallization in both solid and solution phases, while restricting drug release to the pH of the small intestine (ca. 6.8). We demonstrate that ASDs of Nar can be formed using such carboxylated cellulose derivatives as cellulose acetate adipate propionate (CAAdP), carboxymethylcellulose acetate butyrate (CMCAB) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). We compare Nar solution concentrations and release profiles from these cellulosic ASDs to those from pure crystalline Nar, and to Nar ASD in poly(vinylpyrrolidinone) (PVP). We show that all polymers in this study form ASDs with Nar, that the PVP ASDs release Nar at both gastric (1.2) and small intestine (6.8) pH, and that the cellulosic polymers release Nar selectively at neutral pH. Solution concentrations of Nar are significantly enhanced from these ASDs. These preliminary studies indicate that HPMCAS, CAAdP, and CMCAB are practical ASD polymers for Nar due to their ability to generate and stabilize high solution concentrations, and their pH-triggered drug release.     

Thermal behaviour of erythromycin-active substance and tablets

The application of thermal methods is of great importance in the solution of pharmaceutical problems, such as the control of raw materials, the determination of purity, the qualitative and quantitative analysis of drug formulation, tests of thermal stability and compatibility, the determination of kinetic parameters etc. The evaluation of thermal stability in the solid state is mostly made by analyzing their decomposition under isothermal and non-isothermal conditions. This study reports the study on the thermal behaviour of erythromycin-active substance and tablets, respectively, the determination of the kinetic parameters for the decomposition process under non-isothermal conditions. For the determination of kinetic parameters from the TG/DTG curves, were utilized the following methods: Friedman isoconversional, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, Li–Tang, and Kissinger, respectively, a dynamic nitrogen atmosphere and different heating rates: 2.5, 5, 7.5, 10, and 15 °C min^?1. Thermoanalytical curves showed that the active substance is thermally more stable than the tablets and the values of activation energy indicate a considerable thermal stability of active substance. The decrease in stability was attributed to the presence of excipients.     

Prediction of the induction period of crystallization of naproxen in solid dispersion using differential scanning calorimetry

The induction period of crystallization of amorphous naproxen in solid dispersion was measured by DSC. Hydroxypropylmethylcellulose acetate succinate LG (HPMCAS-LG) was selected as a polymer of solid dispersion, because of the excellent inhibitory effect of crystallization. Naproxen was chosen as a model drug having poor water solubility and poor physical stability of glassy state. The prediction of crystallization of amorphous naproxen in solid dispersion at the desired storage temperature or the desired polymer content was carried out. If the storage condition satisfied the requirement that was either more than 90% of HPMCAS-LG content at 333 K or below storage temperature of 301 K for 50% HPMCAS-LG content, the induction period of crystallization of naproxen in solid dispersion would be more than 1 year. The storage period of amorphous drug in solid dispersion of desired storage temperature and desired drug content might be predictable from measurement data of induction period of crystallization.     

Estimation of physical stability of amorphous solid dispersion using differential scanning calorimetry

The physical stability of amorphous drug in solid dispersion was estimated using differential scanning calorimetry (DSC). Tolbutamide (TB) and flurbiprofen (FBP) were selected as insoluble drugs in water. Polyvinylpyrrolidone (PVP) was selected as a polymer for solid dispersion. Solid dispersions of various ratios of TB or FBP and PVP-K25 were prepared by solvent evaporation method and the induction period of crystallization from amorphous drug in solid dispersion was measured by DSC. Compared with FBP, the induction period of crystallization from TB was delayed by an addition of PVP. The improvement of the physical stability by the addition of PVP-K25 was estimated from the activation energy of diffusion of drug molecules and the interfacial free energy between drug crystal and supercooled liquid of drug in solid dispersion. From thses results, the hindrance of the diffusivity of the drug molecule might be mainly affected the delay of the induction period of crystallization of TB and FBP.     

Crystalline inclusion complexes formed between the drug diflunisal and block copolymers

The solid form of drugs plays a central role in optimizing the physicochemical properties of drugs, and new solid forms will provide more options to achieve the desirable pharmaceutical profiles of drugs. Recently, certain drugs have been found to form crystalline inclusion complexes (ICs) with multiple types of linear polymers, representing a new subcategory of pharmaceutical solids. In this study, we used diflunisal (DIF) as the model drug host and extended the guest of drug/polymer ICs from homopolymers to block copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL). The block length in the guest copolymers showed a significant influence on the formation, thermal stability and dissolution behavior of the DIF ICs. Though the PEG block could hardly be included alone, it could indeed be included in the DIF ICs when the PCL block was long enough. The increase of the PCL block length produced IC crystals with improved thermal stability. The dissolution profiles of DIF/block copolymer ICs exhibited gradually decreased aqueous solubility and dissolution rate with the increasing PCL block length. These results demonstrate the possibility of using drug/polymer ICs to modulate the desired pharmaceutical profiles of drugs in a predictable and controllable manner.     

Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV

The evaluation of sildenafil citrate (SC), the best-selling drug for treatment of impotence, for compatibility with various excipients was investigated using thermal and isothermal stress testing. Differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and liquid chromatography (LC) with ultraviolet detection were successfully employed to investigate the compatibility between SC and various excipients commonly used in solid form in the pharmaceutical industry. The studies were performed using 1:1 (m/m) drug/excipient physical mixtures and samples were stored under accelerated stability conditions (40 °C at 75% relative humidity). All excipients tested (such as colloidal silicon dioxide, croscarmellose sodium, lactose, mannitol and sucrose) showed potential incompatibilities by DSC and LC analysis after accelerated stability testing. However, some incompatibilities were not detected by the DSC method and were observed only when LC analysis was performed. HSM was able to differentiate active pharmaceutical ingredient degradation from solubilisation, supporting the interpretation of DSC in excipients where thermal events either overlapped or disappeared. The combination of both the analytical techniques (DSC and LC) and use of a stability chamber is extremely helpful in detecting incompatibilities and providing more robust and accurate approaches for pre-formulation studies.     

Nanosize and microsize clay effects on the kinetics of the thermal degradation of polylactides

Polylactide (PLA)-montmorillonite (MMT) micro- and nanocomposites based on semicrystalline and amorphous polymers and unmodified or organomodified clays at 5 wt% content were produced by melt mixing. Based on the three different test methods that were used to follow thermal degradation, different conclusions were obtained. During melt processing, thermomechanical degradation was more pronounced in the presence of all fillers, which apparently acted catalytically, but to different degrees. During isothermal degradation in air from 180 °C to 200 °C, degradation rate constants were calculated from novel equations incorporating changes in intrinsic viscosity (IV). Results show that the thermal degradation rate constants of the amorphous PLA and its composites are lower than those of the semicrystalline PLA and its composites. Due to better filler dispersion in the polymer matrix, the thermal degradation rate constants of the nanocomposites are significantly lower than those of the unfilled polymers and their microcomposites under air. As per dynamic TGA data and thermal kinetic analysis from weight losses and activation energy calculations, organomodified nanofillers have a complex effect on the polymer thermal stability; the unmodified fillers, however, reduce polymer thermal stability. These TGA data and kinetic analysis results also support the findings that the thermal stability of the amorphous PLA and its composites is higher than that of the semicrystalline polymer and its composites and the thermal stability of the nanocomposites is higher than that of the microcomposites. In general, mathematical modeling based on random thermal scission equations was satisfactory for fitting the TGA experimental data.     

Molecular Simulation and Statistical Learning Methods toward Predicting Drug–Polymer Amorphous Solid Dispersion Miscibility,Stability, and Formulation Design

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API–carrier mixture and the principal API–carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API–carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.     

Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in vivo study

The purpose of this study was establishing a solid dispersion formulation containing a low glass transition temperature (T(g)) and poorly water-soluble drug. Drug/polymer blends with differing physicochemical stabilities and oral absorption were prepared from copolyvidone (PVP-VA), polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) by a hot melt extrusion. HPMC drastically increased the drug oral absorption property, while PVP-VA or PVP stabilized solid dispersions during storage by increasing the T(g) in proportion to polymer concentration. Experimental T(g) values corresponded closely with theoretical T(g) values; indeed, the T(g) values of solid dispersion with HPMC did not increase significantly compared to the T(g) value for the drug alone. A solid dispersion formulation incorporating two different polymers-HPMC and either PVP-VA or PVP-maintained increased T(g), physicochemical stability, solubility, and bioavailability of the solid dispresions owing to each polymer. These findings suggested that both oral absorption and physicochemical stability of low-T(g) drug will be improved using less amount of solid dispersion of combined two polymers than polymer alone.     

Formulation of a Poorly Water-Soluble Drug Sirolimus in Solid Dispersions to Improve Dissolution

An attempt has been made to enhance solubility and dissolution of sirolimus by solid dispersion and complexation technique using various hydrophilic excipients. Sirolimus an immunosuppressant agent has low bioavailability due to its low aqueous solubility. Solid dispersion of sirolimus in PEG-6000, Poloxamer-188, and Mannitol were prepared by fusion and solvent evaporation method. Beta-CD complexation of sirolimus was prepared by kneading method. In vitro dissolution studies were carried out in 0.4% SLS in water, which showed that the solid dispersion containing PEG 6000 (1:1), which was prepared by solvent evaporation method, showed faster dissolution rate than the other formulations and β-cyclodextrin complex. Solid dispersions containing PEG 6000 was further investigated by x-ray powder diffraction, differential scanning calorimetry (DSC), and FTIR. X-ray powder diffraction and DSC patterns suggested that the drug state changed from crystalline to amorphous form in the formulation.     

Thermal characterization and compatibility studies of norfloxacin for development of extended release tablets

Norfloxacin (NFX) is a synthetic antibacterial drug. The development of extended release tablets improves the patients’ comfort and compliance, resulting in lower discontinuation of the therapy; with consequently decrease in bacterial resistance. In the present work, the thermal behavior of NFX was investigated using TG and DSC techniques. Isothermal and non-isothermal methods were employed to determine kinetic data of decomposition process. Compatibility studies between NFX and pharmaceutical excipients, including three hydrophilic polymers were carried out in order to develop a new formulation of NFX to obtain extended release tablets with an approved quality.     

Enhancement of dissolution rate of valdecoxib by solid dispersions technique with PVP K 30 & PEG 4000: preparation and in vitro evaluation

Solid dispersions of valdecoxib were prepared with the objective of dissolution enhancement by melt granulation technique using polyvinyl pyrollidone (PVP K 30) and polyethylene glycol (PEG 4000) alone (1:1) and in combination (1:0.5:0.5). Phase solubility studies showed a linear increase in valdecoxib solubility with increase in polymer concentration in both the cases. The FTIR spectroscopic studies showed the stability of valdecoxib and absence of well defined valdecoxib—PVP K 30–PEG 4000 interaction. Powder X-ray diffraction (XRD) and differential scanning calorimeter (DSC) were used to characterize the solid state of the dispersion, indicated a complete transformation of drug from crystalline to amorphous form. In vitro dissolution studies performed in 0.1 N HCl showed a significant enhance in dissolution rate when PEG 4000 and PVP K 30 were used in combination. Improved drug dissolution by both the carriers may be attributed to the improved wettability, reduction in drug crystallinity and solubilizing effects from solid dispersions of valdecoxib. Accelerated stability studies of solid dispersion with PVP K 30 and PEG 4000 does not show any significant change in the drug content and dissolution profile in 6 months study period. This study concluded that the dissolution rate of valdecoxib can be modulated by appropriate levels of hydrophilic carriers.     

Carvedilol: decomposition kinetics and compatibility with pharmaceutical excipients

Carvedilol (CARVE) is an important cardiovascular drug with limited bioavailability. To improve its therapeutic performance, the investigation of new dosage forms is of great interest due its relevance in clinical applications. Therefore, the aim of this work was to evaluate the stability of CARVE and its drug–excipient compatibility to support its pharmaceutical development. Kinetic analysis under isothermal conditions using thermogravimetry was performed to determine the activation energy of CARVE through an Arrhenius plot. Differential scanning calorimetry, Fourier transform infrared spectroscopy, and optical microscopy were used to test binary mixtures of CARVE and selected excipients. The activation energy of CARVE was 81.2 kJ mol^?1, and from the compatibility studies, all the excipients showed strong thermal interactions, presenting changes in the melting profile of the drug. In addition, analytical assays revealed no physical or chemical changes; because of this, all eight excipients studied are considered compatible and are recommended in formulations containing CARVE. All the evidence together attests to the low chemical reactivity of CARVE and provides useful information for the development of new pharmaceutical formulations containing CARVE.     

Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex

The effects of storage on the crystallization, dissolution and absorption of tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex were investigated, in comparison with those of polyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVP were prepared by a spray-drying method. During storage, a stable form of tolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-beta-CyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamide alone. However, the dissolution rate from the PVP dispersion markedly decreased with storage, because of the formation of slow dissolving form I crystals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflected in the in vivo absorption of tolbutamide and the glucose plasma level after oral administration in dogs. The results suggested that HP-beta-CyD is useful not only for converting crystalline tolbutamide to an amorphous substance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipients such as PVP.     

Miscibility of nifedipine and hydrophilic polymers as measured by (1)H-NMR spin-lattice relaxation

The miscibility of a drug with excipients in solid dispersions is considered to be one of the most important factors for preparation of stable amorphous solid dispersions. The purpose of the present study was to elucidate the feasibility of (1)H-NMR spin-lattice relaxation measurements to assess the miscibility of a drug with excipients. Solid dispersions of nifedipine with the hydrophilic polymers poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose (HPMC) and alpha,beta-poly(N-5-hydroxypentyl)-L-aspartamide (PHPA) with various weight ratios were prepared by spray drying, and the spin-lattice relaxation decay of the solid dispersions in a laboratory frame (T(1) decay) and in a rotating frame (T(1rho) decay) were measured. T(1rho) decay of nifedipine-PVP solid dispersions (3 : 7, 5 : 5 and 7 : 3) was describable with a mono-exponential equation, whereas T(1rho) decay of nifedipine-PHPA solid dispersions (3 : 7, 4 : 6 and 5 : 5) was describable with a bi-exponential equation. Because a mono-exponential T(1rho) decay indicates that the domain sizes of nifedipine and polymer in solid dispersion are less than several nm, it is speculated that nifedipine is miscible with PVP but not miscible with PHPA. All the nifedipine-PVP solid dispersions studied showed a single glass transition temperature (T(g)), whereas two glass transitions were observed for the nifedipine-PHPA solid dispersion (3 : 7), thus supporting the above speculation. For nifedipine-HPMC solid dispersions (3 : 7 and 5 : 5), the miscibility of nifedipine and HPMC could not be determined by DSC measurements due to the lack of obviously evident T(g). In contrast, (1)H-NMR spin-lattice relaxation measurements showed that nifedipine and HPMC are miscible, since T(1rho) decay of the solid dispersions (3 : 7, 5 : 5 and 7 : 3) was describable with a mono-exponential equation. These results indicate that (1)H-NMR spin-lattice relaxation measurements are useful for assessing the miscibility of a drug and an excipient in solid dispersions.     

SYNTHESIS AND CHARACTERIZATION OF HYPERBRANCHED POLY(ESTER-AMIDE)S BASED ON GALLIC ACID AND DL-2-AMINOBUTYRIC ACID

INTRODUCTIONHighly branched macromolecules including dendrimers and hyperbranched polymers are interesting materialswith unique molecular structures and potential applications[1-5]. The two types of polymers have many analogousphysical and chemical properties such as high solubility, low viscosity and abundance of terminal groups. Theformer attracts much attention of researchers due to its perfect monodisperse architecture, but its preparation isgenerally tedious because of various protect…     

Thermotropic phase behaviour of mixed liposomes of archaeal diether and conventional diester lipids

During preformulation studies of pharmaceutical solid dosage forms, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the drug and adjuvants of interest that might interfere with efficacy and safety of the final drug product. Differential scanning calorimetry (DSC) and thermogravimetry (TG) are useful tools for this purpose. The aim of this study was to investigate the thermoanalytical behavior of olanzapine (OLZ) when mixed with several excipients commonly used in solid dosage forms such as microcrystalline cellulose, croscarmellose, dicalcium phosphate dihydrate (DCPD), lactose, magnesium stearate, and povidone. Following DSC and TG analyses, powder X-ray diffraction tests were carried out. Thermoanalytical methods showed evidence of interaction between OLZ and magnesium stearate, lactose, and povidone. These results can be useful during the selection of excipients for pharmaceutical formulation development.