Devitrification of amorphous celecoxib

The purpose of this research was to analyze the devitrification of amorphous celecoxib (CEL) in the presence of different stressors (temperature, pressure, and/or humidity) encountered during processing of solid dosage forms. Amorphous CEL was prepared in situ in the analytical instruments, as well as in laboratory, by quench-cooling of melt process, and analyzed by dynamic mechanical thermal analysis, differential scanning calorimetry, microscopy, and Fourier-transform infrared spectroscopy. Amorphous CEL prepared in situ in the analytical instruments was resistant to crystallization under the influence of temperature and/or pressure, because of its protection from the external environment during preparation. These samples exhibited structural relaxation during annealing at 25°C/0% relative humidity (RH) for 16 hours. Generation of amorphous CEL in the laboratory resulted in partially crystalline samples, because of exposure to environmental temperature and humidity, resulting in incomplete vitrification. Subjection to thermal stress favored crystallization of amorphous CEL into metastable polymorphic forms, which were not obtained by solvent recrystallization approach. Temperature and humidity were identified as the major factors promoting devitrification of amorphous CEL, leading to loss of solubility advantage. Exposure to International Conference on Harmonization-specified accelerated stability storage conditions (40°C/75% RH) resulted in complete devitrification of amorphous CEL within 15 days. The phase-transformation process of amorphous CEL along the temperature scale was examined visually, as well as spectrally. This propensity for devitrification of amorphous CEL seemed to depend on the strength of differential molecular interactions between the amorphous and crystalline form.     

The Stabilization of Amorphous Zopiclone in an Amorphous Solid Dispersion

Zopiclone is a poorly soluble psychotherapeutic agent. The aim of this study was to prepare and characterize an amorphous form of zopiclone as well as the characterization and performance of a stable amorphous solid dispersion. The amorphous form was prepared by the well-known method of quench-cooling of the melt. The solid dispersion was prepared by a solvent evaporation method of zopiclone, polyvinylpyrrolidone-25 (PVP-25), and methanol, followed by freeze-drying. The physico-chemical properties and stability of amorphous zopiclone and the solid dispersion was studied using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray diffractometry (XRD), solubility, and dissolution studies. The zopiclone amorphous solid-state form was determined to be a fragile glass; it was concluded that the stability of the amorphous form is influenced by both temperature and water. Exposure of amorphous zopiclone to moisture results in rapid transformation of the amorphous form to the crystalline dihydrated form. In comparison, the amorphous solid dispersion proved to be more stable with increased aqueous solubility.KEY WORDS: amorphous, fragile, solid dispersion, stability, zopiclone     

Solid State Characterization of Commercial Crystalline and Amorphous Atorvastatin Calcium Samples

Atorvastatin calcium (ATC), an anti-lipid BCS class II drug, is marketed in crystalline and amorphous solid forms. The objective of this study was to perform solid state characterization of commercial crystalline and amorphous ATC drug samples available in the Indian market. Six samples each of crystalline and amorphous ATC were characterized using X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis, Karl Fisher titrimetry, microscopy (hot stage microscopy, scanning electron microscopy), contact angle, and intrinsic dissolution rate (IDR). All crystalline ATC samples were found to be stable form I, however one sample possessed polymorphic impurity, evidenced in XRPD and DSC analysis. Amongst the amorphous ATC samples, XRPD demonstrated five samples to be amorphous ‘form 27’, while, one matched amorphous ‘form 23’. Thermal behavior of amorphous ATC samples was compared to amorphous ATC generated by melt quenching in DSC. ATC was found to be an excellent glass former with T_g/T_m of 0.95. Residual crystallinity was detected in two of the amorphous samples by complementary use of conventional and modulated DSC techniques. The wettability and IDR of all amorphous samples was found to be higher than the crystalline samples. In conclusion, commercial ATC samples exhibited diverse solid state behavior that can impact the performance and stability of the dosage forms.     

Improvement of Physicochemical Properties of an Antiepileptic Drug by Salt Engineering

The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ((1)H) and carbon ((13)C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products.     

Solid-State Characterization and Interconversion of Recrystallized Amodiaquine Dihydrochloride in Aliphatic Monohydric Alcohols

Amodiaquine dihydrochloride monohydrate (AQ-DM) was obtained by recrystallizing amodiaquine dihydrochloride dihydrate (AQ-DD) in methanol, ethanol, and n-propanol. Solid-state characterization of AQ-DD and AQ-DM was performed using X-ray powder diffractometry, Fourier transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. All recrystallized samples were identified as AQ-DM. Crystal habits of AQ-DD and AQ-DM were shown to be needle-like and rhombohedral crystals, respectively. When AQ-DD and AQ-DM were exposed to various relative humidity in dynamic vapor sorption apparatus, no solid-state interconversion was observed. However, AQ-DM showed higher solubility than AQ-DD when exposed to bulk water during solubility study, while excess AQ-DM was directly transformed back to a more stable AQ-DD structure. Heating AQ-DM sample to temperatures ≥190°C induced initial change to metastable amorphous form (AQ-DA) which was rapidly recrystallized to AQ-DD upon ≥80%RH moisture exposure. AQ-DD was able to be recrystallized in alcohols (C1-C3) as AQ-DM solid-state structure. In summary, AQ-DM was shown to have different solubility, moisture and temperature stability, and interconversion pathways when compared to AQ-DD. Thus, when AQ-DM was selected for any pharmaceutical applications, these critical transformation and property differences should be observed and closely monitored.     

Coamorphous Loratadine-Citric Acid System with Enhanced Physical Stability and Bioavailability

Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T _g over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T _g over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.     

Preparation and Characterization of Co-Grinded Mixtures of Aceclofenac and Neusilin US2 for Dissolution Enhancement of Aceclofenac

The present study was carried out with a view to enhance the dissolution of poorly water-soluble BCS-class II drug aceclofenac by co-grinding with novel porous carrier Neusilin US_2. (amorphous microporous granules of magnesium aluminosilicate, Fuji Chemical Industry, Toyama, Japan). Neusilin US₂ has been used as an important pharmaceutical excipient for solubility enhancement. Co-grinding of aceclofenac with Neusilin US₂ in a ratio of 1:5 was carried out by ball milling for 20 h. Samples of co-ground mixtures were withdrawn at the end of every 5 h. and characterized for X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. The analysis revealed the conversion of crystalline aceclofenac to its amorphous form upon milling with Neusilin US₂. Further, in vitro dissolution rate of aceclofenac from co-ground mixture was significantly higher compared to pure aceclofenac. The accelerated stability study of co-ground mixture was carried out at 40°C/75%RH for 4 weeks, and it showed that there was no reversion from amorphous to crystalline form. Thus, it is advantageous to use a porous carrier like Neusilin US₂ in improvement of dissolution of poorly soluble drugs.     

Study of the Transformations of Micro/Nano-crystalline Acetaminophen Polymorphs in Drug-Polymer Binary Mixtures

This study elucidates the physical properties of sono-crystallised micro/nano-sized acetaminophen/paracetamol (PMOL) and monitors its possible transformation from polymorphic form I (monoclinic) to form II (orthorhombic). Hydrophilic Plasdone® S630 copovidone (S630), N-vinyl-2-pyrrolidone and vinyl acetate copolymer, and methacrylate-based cationic copolymer, Eudragit® EPO (EPO), were used as polymeric carriers to prepare drug/polymer binary mixtures. Commercially available PMOL was crystallised under ultra sound sonication to produce micro/nano-sized (0.2–10 microns) crystals in monoclinic form. Homogeneous binary blends of drug-polymer mixtures at various drug concentrations were obtained via a thorough mixing. The analysis conducted via the single X-ray crystallography determined the detailed structure of the crystallised PMOL in its monoclinic form. The solid state and the morphology analyses of the PMOL in the binary blends evaluated via differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), scanning electron microscopy (SEM) and hot stage microscopy (HSM) revealed the crystalline existence of the drug within the amorphous polymeric matrices. The application of temperature controlled X-ray diffraction (VTXRPD) to study the polymorphism of PMOL showed that the most stable form I (monoclinic) was altered to its less stable form II (orthorhombic) at high temperature (>112°C) in the binary blends regardless of the drug amount. Thus, VTXRD was used as a useful tool to monitor polymorphic transformations of crystalline drug (e.g. PMOL) to assess their thermal stability in terms of pharmaceutical product development and research.     

Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation

A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K₃LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K₃LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy, and Fourier-transform infrared spectroscopy. In vitro–in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM.     

Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine

Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron® tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained >?84% CN in solution while Stugeron® tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat® Smartseal 30D) showed robust stability and maintained >?97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs.     

A Method to Evaluate the Effect of Contact with Excipients on the Surface Crystallization of Amorphous Drugs

Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while d-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.KEY WORDS: amorphous, drugs, growth rate, nucleation rate, tablet excipients     

Investigating the Principles of Recrystallization from Glyceride Melts

Different lipids were melted and resolidified as model systems to gain deeper insight into the principles of recrystallization processes in lipid-based dosage forms. Solid-state characterization was performed on the samples with differential scanning calorimetry and X-ray powder diffraction. Several recrystallization processes could be identified during storage of the lipid layers. Pure triglycerides that generally crystallize to the metastable α-form from the melt followed by a recrystallization process to the stable β-form with time showed a chain-length-dependent behavior during storage. With increasing chain length, the recrystallization to the stable β-form was decelerated. Partial glycerides exhibited a more complex recrystallization behavior due to the fact that these substances are less homogenous. Mixtures of a long-chain triglyceride and a partial glyceride showed evidence of some interaction between the two components as the partial glyceride hindered the recrystallization of the triglyceride to the stable β-form. In addition, the extent of this phenomenon depended on the amount of partial glyceride in the mixture. Based on these results, changes in solid dosage forms based on glycerides during processing and storage can be better understood.     

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.     

Influence of β-cyclodextrin on the Properties of Norfloxacin Form A

Cyclodextrins are able to form host–guest complexes with hydrophobic molecules to result in the formation of inclusion complexes. The complex formation between norfloxacin form A and β-cyclodextrin was studied by exploring its structure affinity relationship in an aqueous solution and in the solid state. Kneading, freeze-drying, and physical mixture methods were employed to prepare solid complexes of norfloxacin and β-cyclodextrin. The solubility of norfloxacin significantly increased upon complexation with β-cyclodextrin as demonstrated by a solubility isotherm of the A_L type along with the results of an intrinsic dissolution study. The complexes were also characterized in the solid stated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffractometry, scanning electron microscopy (SEM), and solid-state nuclear magnetic resonance (ssNMR) spectrometry. The thermal analysis showed that the thermal stability of the drug is enhanced in the presence of β-cyclodextrin. Finally, the microbiological studies showed that the complexes have better potency when compared with pure drug.KEY WORDS: bioassay, complexation, intrinsic dissolution, norfloxacin, β-cyclodextrin     

Preparation and Evaluation of Solid Dispersions of A New Antitumor Compound Based on Early-Stage Preparation Discovery Concept

Ensuring sufficient drug solubility is a crucial problem in pharmaceutical-related research. For water-insoluble drugs, various formulation approaches are employed to enhance the solubility and bioavailability of lead compounds. The goal of this study was to enhance the dissolution and absorption of a new antitumor lead compound, T-OA. Early-stage preparation discovery concept was employed in this study. Based on this concept, a solid dispersion system was chosen as the method of improving drug solubility and bioavailability. Solid dispersions of T-OA in polyvinylpyrrolidone (PVP) K30 were prepared by the solvent evaporation method. Dissolution testing determined that the ideal drug-to-PVP ratio was 1:5. X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were employed to confirm the formation of solid dispersions. Scanning electron microscopy demonstrated that T-OA was converted into an amorphous form. Both in vitro dissolution testing and the in vivo studies demonstrated that the solubility and bioavailability of T-OA were significantly improved when formulated in a solid dispersion with PVP. The dissolution rate of the T-OA/PVP solid dispersion was greatly enhanced relative to the pure drug, and the relative bioavailability of T-OA solid dispersions was found to be 392.0%, which is 4-fold higher than the pure drug.     

Preformulation Study of the Inclusion Complex Irbesartan-β-Cyclodextrin

The aim of the present work was to improve the solubility and dissolution profile of Irbesartan (IRB), a poorly water-soluble drug by formation of inclusion complex with β-cyclodextrin (βCD). Phase solubility studies revealed increase in solubility of the drug upon cyclodextrin addition, showing A_L—type of graph with slope less than one indicating formation of 1:1 stoichiometry inclusion complex. The stability constant (K _s) was found to be 104.39 M⁻¹. IRB–βCD binary systems were prepared by cogrinding, kneading using alcohol, kneading using aqueous alcohol, and coevaporation methods. Characterization of the binary systems were carried out by differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and proton nuclear magnetic resonance. The dissolution profiles of inclusion complexes were determined and compared with those of IRB alone and physical mixture. Among the various methods, coevaporation was the best in which the solubility was increased and dissolution rate of the drug was the highest. The study indicated the usefulness of cyclodextrin technology to overcome the solubility problem of IRB.     

Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins

Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using ¹H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, β-cyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.KEY WORDS: antifungal, BCS class II, dissolution rate, insoluble, itraconazole     

Metastability and transformation of polymorphic crystals in biodegradable poly(butylene adipate)

Polymorphism phenomenon of melt-crystallized poly(butylene adipate) (PBA) has been studied by wide-angle X-ray diffraction (WAXD), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). It has been found that the isothermal crystallization leads to the formation of PBA polymorphic crystals, simply by changing the crystallization temperature. The PBA alpha crystal, beta crystal, and the mixture of two crystal forms grow at the crystallization temperatures above 32 degrees C, below 27 degrees C, and between these two temperatures, respectively. The relationship between PBA polymorphism and melting behaviors has been analyzed by the assignments of multiple melting peaks. Accordingly, the equilibrium melting temperatures Tm degrees of both alpha and beta crystals were determined by Hoffman-Weeks and Gibbs-Thomson equations for the purpose of understanding the structural metastability. The Tm degrees of the PBA alpha crystal was found to be higher than that of the beta crystal, indicating that the PBA alpha crystal form is a structurally stable phase and that the beta crystal form is a metastable phase. The analysis of growth kinetics of PBA polymorphic crystals indicates that the metastable PBA beta crystal is indeed the kinetically preferential result. Based on the thermal and kinetic results, the phenomenon of stability inversion with crystal size in melt-crystallized PBA was recognized, in terms of the growth mechanisms of PBA alpha and beta crystals and the transformation of beta to alpha crystals. The PBA beta --> alpha crystal transformation takes place at a sufficiently high annealing temperature, and the transformation has been evident to be a solid-solid-phase transition process accompanied by the thickening of lamellar crystals. The molecular motion of polymer chains in both crystalline and amorphous phases has been discussed to understand the thickening and phase transformation behaviors.     

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

The aim of this paper is to investigate the physicochemical properties of binary amorphous dispersions of poorly soluble sulfonamide/polymeric excipient prepared by ball milling. The sulfonamides selected were sulfathiazole (STZ), sulfadimidine (SDM), sulfamerazine (SMZ) and sulfadiazine (SDZ). The excipients were polyvinylpyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, commercially known as Soluplus®. Co-milled systems were characterised by powder X-ray diffraction and differential scanning calorimetry. PVP was shown to form amorphous dispersions over a wider composition range than Soluplus® for the four sulfonamides tested. Moreover, amorphous dispersions made with PVP were homogeneous [single glass transition (Tg)], while amorphous dispersions made from Soluplus® were heterogeneous (two Tgs). This behaviour is consistent with the fact that all the sulfonamides tested presented a lower solubility in Soluplus® than in PVP, as evidenced by Flory–Huggins parameters determined. Amorphous dispersions of SDM with Soluplus® could be produced even though SDM does not amorphise alone upon milling and Soluplus® presents Tg at a lower temperature than SDM. Amorphous dispersions of SMZ could be prepared with a lower excipient concentration compared to STZ, SDM and SDZ, which may reflect the one-dimensional H-bonding network in SMZ compared to the 2D or 3D H-bonding network found in the other sulfonamides. Stability tests (60% RH/25°C) revealed that dispersions made with Soluplus® remained dry and powdery compared to those made with PVP that formed a sticky paste in less than 2 weeks, indicating a possible advantage of using Soluplus® in terms of increased physical stability under high humidity storage conditions.     

Advanced Technologies for Oral Controlled Release: Cyclodextrins for Oral Controlled Release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability, and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug–drug or drug–additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.