Metastable Racemic Ibuprofen Supercooled Liquid

Zhang J., Jiang Q., Xu Z., Yang Q., Hao G., Liu M., Zeng Z.

Ivone M., Denora N., D'Amico V., Mareczek L., Mueller L.K., Arduino I., Ambruosi A., Lopedota A.A.

Poly(vinyl alcohol) (PVA) is a widely used synthetic polymer and due to its hydrophilicity, biocompatibility, and biodegradability, it is considered a suitable polymer for the formulation of drug delivery systems. In this study, PVA was used in a prilling/vibration technology as a pharmaceutical grade excipient to produce microbeads for oral administration that improve class II drugs' solubility and dissolution rate according to the Biopharmaceutical Classification System (BCS). Specifically, Ibuprofen (IBU) is a weakly acidic drug with low solubility at pH 1.2 and Ketoconazole (KETO), a weakly basic drug characterized by low solubility at pH 6.8. These drugs were selected because of their requirements for specific dosing conditions in children or animals, which often differ from commercially available conventional drugs. The microbeads produced were fully characterized in terms of drug loading, encapsulation efficiency, size, morphology, and drug release experiments were also conducted in a gastric fluid for IBU-loaded microbeads and simulated intestinal fluid for KETO-loaded microbeads. Finally, PVA microbeads were compared with an amorphous solid dispersion (ASDs) of the respective APIs, showing the same increase in solubility and dissolution rate. Therefore, the use of the prilling/vibration technology to produce PVA-based microbeads containing BCS class II drugs improves solubility and dissolution profile, which represent fundamental requirements for good bioavailability. Furthermore, the manufactured microbeads provide a high degree of dosing flexibility, making them suitable for administration in pediatric or veterinary patients with swallowing difficulties and requiring customized dosing.

Logacheva K., Gergelezhiu P., Raksha E., Savostina L., Arzumanyan G., Eresko A., Malakhov S., Mamatkulov K., Ponomareva O., Belushkin A., Chudoba D.

Vibrational spectroscopic features of ibuprofen and ketoprofen (non-steroidal anti-inflammatory drugs) were determined as a result of joint analysis of experimental and DFT-calculated data. There is a good agreement between the experimental (IR, Raman) and calculated (BP86/def2-SVP) vibrational frequencies of ibuprofen and ketoprofen.

Marks J.A., Nichols B.L., Mosquera-Giraldo L.I., Yazdi S., Taylor L.S., Edgar K.J.

Uddin A., Halder S., Deb N., Das H., Shuma M.L., Hasan I., Shill M.C., Haider S.S.

This study aims to improve the biopharmaceutical, mechanical, and tableting properties of a poorly soluble drug, ibuprofen (IBP), by preparing amorphous solid dispersion (ASD) followed by a sustained-release tablet formulation. A suitable polymer to develop an ASD system was chosen by utilizing the apparent solubility of IBP in various polymer solutions. ASDs containing various ratios of IBP and selected polymer were prepared by the melt fusion (MF) method. ASD containing optimized drug-polymer ratio prepared by freeze-drying (FD) method was characterized and compared physicochemically. The solubility of IBP in water increased 28-fold and 35-fold when formulated as ASD by MF and FD, respectively. Precise formulations showed amorphization of IBP and increased surface area, improving solubility. The dissolution pattern of optimized ASD-IBP in pH 6.8 phosphate buffer after 60 min in MF and FD was enhanced 3-fold. In addition, direct compression tablets comprising optimized ASD granules from MF and FD were made and assessed using compendial and noncompendial methods. ASD-IBP/MF and ASD-IBP/FD formulations showed a similar drug release profile. In addition, 12 h of sustained IBP release from the ASD-IBP-containing tablets was obtained in a phosphate buffer with a pH of 6.8. From the dissolution kinetics analysis, the Weibull model fitted well. The drug release pattern indicated minimal variations between tablets formed using ASD-IBP prepared by both procedures; however, pre- and postcompression assessment parameters differed. From these findings, the application of ASD and sustained-release polymers in matrix formation might be beneficial in improving the solubility and absorption of poorly soluble drugs such as IBP.

Chen L., Hu E., Shen P., Qian S., Heng W., Zhang J., Gao Y., Wei Y.

This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer’ matrix ratios and drug release behaviors. Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

Ren S., Nian F., Chen X., Xue R., Chen F.

Two routes of the dehydration process of theophylline monohydrate have been proposed in this work from mid-frequency Raman difference spectra (MFRDS) results and experiments. MFRDS can establish short-range order correlations among various theophylline crystal forms. MFRDS results indicate that the short-range order of metastable Form III is most similar to that of monohydrate, which explains that Form III is the main dehydration products in the mild dehydration process. The phenomenon that unstable amorphous theophylline intermediate phase would appear during the dehydration process of theophylline monohydrate was confirmed indirectly by Powder X-ray Diffraction (PXRD) and optical microscope and reported in the previous reports, which could cause the nucleation of Form II, as MFRDS results indicate short-range order of amorphous solid dispersion of theophylline is most similar to that of Form II. MFRDS analysis shows the advantages in studying the phase transformation of small organic molecule crystals.

Kirkham J., Korter T.M., Be̅rziņš K., McGoverin C.M., Gordon K.C., Fraser-Miller S.J.

Guinet Y., Paccou L., Hédoux A.

Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical stability of amorphous drugs within the formulation. Ibuprofen is commonly used in topical formulations and then was selected as a model drug. Additionally, its low Tg allows easy, unexpected recrystallization at room temperature with negative consequence on skin penetration. In this study, the physical stability of amorphous ibuprofen was investigated in two types of formulations: (i) in terpenes-based deep eutectic solvents (DES) and (ii) in arginine-based co-amorphous blends. The phase diagram of ibuprofen:L-menthol was mainly analyzed by low-frequency Raman spectroscopy, leading to the evidence of ibuprofen recrystallization in a wide range of ibuprofen concentration. By contrast, it was shown that amorphous ibuprofen is stabilized when dissolved in thymol:menthol DES. Forming co-amorphous arginine–ibuprofen blends by melting is another route for stabilizing amorphous ibuprofen, while recrystallization was detected in the same co-amorphous mixtures obtained by cryo-milling. The mechanism of stabilization is discussed from determining Tg and analyzing H-bonding interactions by Raman investigations in the C=O and O–H stretching regions. It was found that recrystallization of ibuprofen was inhibited by the inability to form dimers inherent to the preferential formation of heteromolecular H-bonding, regardless of the glass transition temperatures of the various mixtures. This result should be important for predicting ibuprofen stability within other types of topical formulations.

Fan Y., Liang C., Li Y., Xiao W., Niu Y., Jin H., Xue R., Chen F.

The selective crystallization behaviours of amorphous boscalid (BOS), BOS monohydrate and acetone/ethyl acetate/ethanol/methanol solutions are explained and predicted by mid-frequency Raman difference spectra analysis. The phase transition processes including solutions...

Lapuk S., Ponomareva M., Ziganshin M., Larionov R., Mukhametzyanov T., Schick C., Lounev I., Gerasimov A.

The dynamic glass transition temperatures, the mean temperature fluctuations, and the size of the cooperatively rearranging regions of polyvinylpyrrolidone with different molecular masses were determined using DSC, FSC, and BDS.

Moutamenni B., Tabary N., Mussi A., Dhainaut J., Ciotonea C., Fadel A., Paccou L., Dacquin J., Guinet Y., Hédoux A.

Mesoporous silica (MPS) carriers are considered as a promising strategy to increase the solubility of poorly soluble drugs and to stabilize the amorphous drug delivery system. The development by the authors of a solvent-free method (milling-assisted loading, MAL) made it possible to manipulate the physical state of the drug within the pores. The present study focuses on the effects of the milling intensity and the pore architecture (chemical surface) on the physical state of the confined drug and its release profile. Ibuprofen (IBP) and SBA-15 were used as the model drug and the MPS carrier, respectively. It was found that decreasing the milling intensity promotes nanocrystallization of confined IBP. Scanning electron microscopy and low-frequency Raman spectroscopy investigations converged into a bimodal description of the size distribution of particles, by decreasing the milling intensity. The chemical modification of the pore surface with 3-aminopropyltriethoxisylane also significantly promoted nanocrystallization, regardless of the milling intensity. Combined analyses of drug release profiles obtained on composites prepared from unmodified and modified SBA-15 with various milling intensities showed that the particle size of composites has the greatest influence on the drug release profile. Tuning drug concentration, milling intensity, and chemical surface make it possible to easily customize drug delivery.

Berthier L., Reichman D.R.

The physics of the glass transition and amorphous materials continues to attract the attention of a wide research community after decades of effort. Supercooled liquids and glasses have been studied numerically since the advent of molecular dynamics and Monte Carlo simulations, and computer studies have greatly enhanced both experimental discoveries and theoretical developments. In this Review, we provide a modern perspective on this area. We describe the need to go beyond canonical methods when studying the glass transition — a problem that is notoriously difficult in terms of timescales, length scales and physical observables. We summarize recent algorithmic developments to achieve enhanced sampling and faster equilibration by using replica-exchange methods, cluster and swap Monte Carlo algorithms, and other techniques. We then review some major advances afforded by these tools regarding the statistical mechanical description of the liquid-to-glass transition, and the mechanical, vibrational and thermal properties of the glassy solid. Computer simulations may unlock crucial aspects of how a liquid transforms into a glass, but are hampered by rapidly growing relaxation times near the transition. This Review summarizes progress towards overcoming this problem and creating realistic in silico glasses, and discusses what understanding has been enabled.

Chen F., Yang C., Cheng X., Fan Y., Chen X., Ren S., Xue R.

The experimental phenomena that amorphous inosine (IR), α-IR, and IR dihydrate can form from IR aqueous solution and β-IR can crystallize from IR 70 vol% DMSO aqueous solution were explained using mid-frequency Raman difference spectra analysis.

Patel N.G., Serajuddin A.T.

Moisture plays a critical role in the stability of amorphous solid dispersions (ASD) as it can lower the glass transition temperature (Tg) and thereby increase molecular mobility resulting in drug crystallization. A systematic study on moisture sorption by four polyvinylpyrrolidone (PVP) having different molecular weights (Kollidon® 12, 17, 30, and 90) and two related copolymers (Kollidon® VA64; Soluplus®) was conducted at 25 and 40 °C as a function of relative humidity to determine effects of absorbed moisture on Tg and potential stability of ASDs. A VTI dynamic moisture sorption analyzer was used, where experimental conditions were first established such that equilibrium was reached and there was no significant hysteresis loop between sorption and desorption isotherms. The PVPs had identical moisture sorption profiles and were highly hygroscopic, reaching 22-24% and 41-42% w/w moisture at 25 °C/60% RH and 25 °C/80% RH, respectively. Kollidon® VA64 and Soluplus® were relatively less hygroscopic, reaching, respectively, about half and one-fourth the moisture content of PVPs at 25 °C/60% RH. Moisture sorption at 40 °C was relatively lower than that at 25 °C. The high moisture sorption drastically decreased Tg of polymers, which roughly agreed with theoretical calculations based on the Gordon-Taylor/Kelley-Bueche equation, although deviation occurred, possibly due to hydrogen bonding between polymer and moisture.