Water-soluble Active Pharmaceutical Ingredients Research Articles

Factors Influencing the Crystallization-Onset Time of Metastable ASDs.

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon–Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as “larger particles always crystallize later than smaller particles” are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.

Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion.

Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.

Enteric and hydrophilic polymers enhance dissolution and absorption of poorly soluble acidic drugs based on micro-environmental pH-modifying solid dispersion

The oral bioavailability of poorly water-soluble active pharmaceutical ingredient (API) is often inadequate for the desired therapeutic effect. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is an effective method for enhancing the dissolution of pH-dependent soluble APIs. However, erratic bioavailability of these drugs was often found when the micro pHm SD of the drugs was orally administrated and passed through the gastrointestinal tract. Because the added alkalizer in micro pHm SD could be neutralized by the acid in the stomach, as a result not enough alkalizer is left to form alkaline micro-environment around the drug in the intestine, leading to poor dissolution and bioavailability of API. Enteric polymers are applicable materials for site-specific drug delivery that are insoluble in gastric tract but soluble in the intestine targeted for drug release. In this study, a poorly water-soluble model drug, toltrazuril (TOL), was prepared as enteric micro pHm SD with enteric, hydrophilic polymers and alkalizer. The surface of enteric micro pHm SD tablets staining and alkalizer protection test in the acid dissolution medium qualitatively and quantitatively confirmed the protective effects of the enteric polymer on the alkalizer. Dissolution studies revealed that the drug release from the enteric micro pHm SDs was improved significantly compared with micro pHm SD with no enteric polymer. The pH-dependent solubility of enteric polymer had effects on the dissolution of APIs from the SDs in neutral medium. Enteric micro pHm SDs with higher proportion of enteric polymer showed higher Cmax and dissolution rate of TOL. The physicochemical characterization and the molecular interaction between drug and matrix were analyzed by electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR), finding that the formation of hydrogen bonds between TOL and matrix was helpful to promote dissolution of TOL. Ca(OH)2-TOL-PVPk30-HPMCAS 8: 8: 18: 6 was determined as the most optimal enteric micro pHm SD, which significantly improved the bioavailability of TOL and its active metabolism (TOLSO, TOLSO2) in pharmacokinetic study and could effectively reduce the irritation of the gastrointestinal mucosa caused by the alkalizer Ca(OH)2 when the SD was orally administrated to rabbits. The present study demonstrates that formulating APIs with poor water solubility as enteric micro pHm SD is an effective method for protecting the alkalizer in SD and improving the dissolution of APIs and the bioavailability following oral administration.

Drug Amorphous Solid Dispersions Based on Poly(vinyl Alcohol): Evaluating the Effect of Poly(propylene Succinate) as Plasticizer.

Although significant actions have been taken towards the utilization of poly(vinyl alcohol) (PVA) in the preparation of drug amorphous solid dispersions (ASDs) using fusion-based techniques (such as melt-quench cooling and hot-melt extrusion), several drawbacks regarding its rather high melting temperature and its thermal degradation profile make the use of the polymer extremely challenging. This is especially important when the active pharmaceutical ingredient (API) has a lower melting temperature (than PVA) or when it is thermally labile. In this vein, a previous study showed that newly synthesized polyester-based plasticizers may improve the processability and the thermal properties of PVA. However, the effects of such polyester-based plasticizers on the drug’s physicochemical and pharmaco-technical properties are yet unknown. Hence, the aim of the present study is to extend our previous findings and evaluate the use of poly(propylene succinate) (PPSu, i.e., the most promising plasticizer in regard to PVA) in the preparation of drug-loaded PVA-based ASDs. Dronedarone (DRN), a poorly water-soluble API, was selected as a model drug, and drug ASDs (using either neat PVA or PVA-PPSu) were prepared using the melt-mixing/quench cooling approach at low melting temperatures (i.e., 170 °C). DSC and pXRD analysis showed that a portion of the API remained crystalline in the ASDs prepared only with the use of neat PVA, while the samples having PPSu as a plasticizer were completely amorphous. Further evaluation with ATR-FTIR spectroscopy revealed the formation of significant intermolecular interactions between the API and the PVA-PPSu matrix, which could explain the system’s physical stability during storage. Finally, dissolution studies, conducted under nonsink conditions, revealed that the use of PVA-PPSu is able to maintain DRN’s sustained supersaturation for up to 8 h.

Evaluation of drug release kinetics from polymeric nanoparticles loaded with poorly water-soluble APIs

Abstract The aim of this research was to investigate the release behavior of a combination of two poorly water-soluble active pharmaceutical ingredients (APIs) from poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles. Amlodipine besylate - AML, a calcium channel blocker, and valsartan - VAL, an angiotensin II receptor antagonist drug, were used as poorly water-soluble model drugs. PLGA nanoparticles loaded with AML-VAL (1:16 w/w) were obtained by nanoprecipitation using an amphiphilic block copolymer - Pluronic F127 as stabilizer. The drugs release from the PLGA nanoparticles was determined by a dialysis membrane method under sink conditions. Nanoparticles provided a slow release for both APIs and an attenuated burst effect compared to free drug. Five kinetics models such as Zero-order, First-order, Korsmeyer-Peppas, Higuchi and Hixson-Crowell were applied to predict drug release profiles. The Higuchi and Korsmeyer-Peppas models (R2 > 0.97) best described physicochemical release phenomenon for each PLGA formulations.

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.

Influence of process and formulation parameters on the preparation of solid lipid nanoparticles by dual centrifugation

A promising strategy to formulate poorly water-soluble active pharmaceutical ingredients (APIs) is the application of these substances in solid lipid nanoparticles. These drug carrier systems are commonly prepared by high-pressure homogenization above the melting temperature of the utilized lipid. While being very useful for large-scale production this method is quite resource-consuming and does not allow simultaneous processing of multiple samples, e.g. for screening purposes. For this reason, an alternative manufacturing process, dual centrifugation, is introduced to prepare solid lipid nanoparticles. The ingredients of the dispersions were directly weighed into 2 mL vessels at room temperature without the need to prepare a pre-mix emulsion. Due to an additional rotation of the samples in the heated centrifuge as well as the addition of grinding media an intensive stressing of the samples was achieved. The emulsification process was finished within 10 min with sample temperatures of up to 90 °C being obtained. Dependent on the process set-up like grinding media size, filling ratio or process temperature and the composition of the lipid formulation, the achieved particles sizes were below 200 nm and had a narrow, monomodal size distribution.

Crystallization Risk Assessment of Amorphous Solid Dispersions by Physical Shelf-Life Modeling: A Practical Approach.

Amorphous solid dispersions (ASDs) of a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can enhance the water solubility and therefore generally improve the bioavailability of the API. Although examples of long-term stability are emerging in the literature, many ASD products are kinetically stabilized, and inhibition of crystallization of a drug substance within and beyond shelf life is still a matter of debate, since, in some cases, the formation of crystals may impact bioavailability. In this study, a risk assessment of API crystallization in packaged ASD drug products and a mitigation strategy are outlined. The risk of shelf-life crystallization and the respective mitigation steps are assigned for different drug product development scenarios and the scientific principles of each step are discussed. Ultimately, the physical stability of ASD drug products during shelf-life storage is modeled. The methodology is based on the quantification of crystal growth kinetics by transmission Raman spectroscopy (TRS), modeling the impact of water sorption on the glass-transition temperature of the ASD, and the prediction of moisture uptake by the packaged ASD drug product during storage. This approach is applied to an ASD of fenofibrate that features both fast API crystallization under accelerated storage conditions and long-term stability in a suitable protective packaging under conventional storage conditions.

Precipitation from amorphous solid dispersions in biorelevant dissolution testing: The polymorphism of regorafenib

Amorphous Solid Dispersions (ASDs) are a major drug formulation technique to achieve higher bioavailability for poorly water-soluble active pharmaceutical ingredients. So far, dissolution tailoring and supersaturation enhancement have been studied in detail, whereas less is known about the importance of formed precipitates with amorphous or crystalline states at the site of drug absorption.Regorafenib monohydrate (RGF MH), a multikinase inhibitor drug categorized as Biopharmaceutics Classification System (BCS) class II compound, was formulated with povidone K25 and hypromellose acetate succinate (HPMCAS) as an ASD. Here, for the first time, the RGF precipitation process as well as the physicochemical properties of the arising precipitates are investigated. The formed precipitates from biorelevant dissolution showed varying drug content and were analyzed offline by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), confocal Raman microscopy (CRM), X-ray powder diffraction (XRPD), and small angle X-ray scattering (SAXS). In addition to different crystalline RGF precipitates, an amorphous co-precipitate of RGF and HPMCAS was identified, which was suppressed in the presence of PVP. Wide angle X-ray scattering (WAXS) and isothermal calorimetry (ITC) were used to track the precipitation process of RGF in-situ. From calorimetric data, the precipitation profile was calculated. RGF forms precipitates in multiple polymorphic states dependent on the environmental conditions, i.e., dissolution media composition and chosen excipients. The engineered formation of defined amorphous structures in-vivo may be a promising future drug formulation strategy.

Influence of the pK a Value of Cinnamic Acid and P-Hydroxycinnamic Acid on the Solubility of a Lurasidone Hydrochloride-Based Coamorphous System.

Coamorphization of a poorly water-soluble active pharmaceutical ingredient (API) has been proven to be effective in improving its solubility. Generally, API can form multiple coamorphous systems with different coformers. However, it remains unclear how the pKa value of different coformers influences the solubility of the API. In this study, structurally related cinnamic acid (CA, pKa = 4.37) and p-hydroxycinnamic acid (pHCA, pKa = 4.65) were chosen as coformers for the coamorphization of lurasidone hydrochloride (LH). To investigate the influence of the pKa value of the coformers on the solubility of LH, LH-CA/pHCA coamorphous systems were prepared by the vacuum rotary evaporation method and characterized by powder X-ray diffraction and differential scanning calorimetry. Fourier-transform infrared spectroscopy, Raman spectroscopy, and molecular dynamics (MD) simulations were employed to investigate the intermolecular interaction of the coamorphous systems. It was found that the solubility of LH in the coamorphous LH–pHAC with a higher-pKa coformer was higher than that of the coamorphous LH-CA. In addition, according to the solubility product principle-based formula derivation, we established the functional relationship between the solubility of LH and the pKa of the coformers at different-pH buffering solution. It was found that the coformer with a larger pKa value would be more beneficial to improve the solubility profile of LH. Collectively, the current study offers an effective strategy to improve the poor solubility of drugs by increasing the pKa value of the coformer in coamorphous systems.

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol\xae Dispersing

Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.

Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers.

The development of amorphous solid dispersions (ASDs) is one way to overcome the bioavailability challenges of poorly water-soluble active pharmaceutical ingredients (APIs). An important consideration with ASD systems is that crystallization can occur during preparation, storage, and dissolution, thus reducing their bioavailability advantage. Currently, it is unclear whether the dissolution characteristics of the polymer carrier affects the dissolution performance of ASDs with intrinsic crystallization. Our aim was to differentiate the impact of a minor amount of intrinsic crystallinity (up to 10%) within soluble and insoluble carriers on ASD performance, using the area under the curve (AUC) values of non-sink dissolution profiles as a measure of dissolution performance that can inform in vivo bioavailability. In order to discern such differences, itraconazole (ITZ) ASDs were prepared by Hot Melt Extrusion (HME) with 50% (w/w) drug loading. PVP K12 and HPMCAS were used as the soluble and insoluble carriers in pH 1.2 dissolution media, respectively. Dissolution was also conducted in pH 6.8 buffer, wherein HPMCAS becomes soluble, to cross-validate experimental observations. Crystalline content was determined by differential scanning calorimetry (DSC) prior to dissolution. Soluble polymers differed from insoluble polymers in that crystals formed during processing and storage were released during dissolution which can undergo further growth causing a sharp decline in drug concentration in the dissolution medium. This led to a significant decrease in the AUC for soluble ASDs containing intrinsic crystallinity. In contrast, insoluble polymer carriers did not release the intrinsically formed crystals and the impact of subsequent crystal growth on dissolution performance was minimal for insoluble ASD systems. Furthermore, physical mixtures with spiked crystallinity were only found to reflect the dissolution performance of soluble ASDs exhibiting intrinsic crystallinity. Thus, in considering the impact of intrinsic crystallinity on ASD performance, the nature of the polymeric carrier in terms of solubility characteristics needs to be taken into account as there is significantly more variation in AUC with soluble carriers than insoluble carriers exhibiting intrinsic crystallinity.

Influence of shellac on the improvement of solubility and supersaturation of loratadine amorphous solid dispersion using a new grade of HPMC

The use of ternary amorphous solid dispersions (ASDs) comprised of surfactants and synthetic polymers to improve the solubility of low water soluble active pharmaceutical ingredients (APIs) have been widely investigated as an emerging concept. Shellac is used as complex resin for coating purposes, but to the best of our knowledge, the use of shellac as natural excipient in ASDs has not been reported. The current study has sought to prepare binary and ternary ASDs of shellac, alone or in combination with HPMC, with the model API loratadine (LOR) via spray drying and hot melt extrusion to achieve solubility improvement and supersaturation maintenance. The ASDs were characterized and tested for their in-vitro dissolution performance. Among various shellac fractions within the ternary ASDs, the 10% weight fraction was found to increase the solubility 30 folds and maintain the supersaturation for 3 h compared to other binary and ternary formulations. This superiority was due to specific and stronger API matrix interactions detected via ATR-IR, which was further studied in terms of stability. It was found that there exists a correlation between the amount of the dissolved API and the API crystallinity, which dictates the level of supersaturation. While the crystallinity is set by the LOR concentration at the end of the test, the dissolution rate depended on the origin of the crystals.

Microwave induced dielectric heating for the on-demand development of indomethacin amorphous solid dispersion tablets

The poor aqueous solubility of drugs challenges their pharmaceutical development and oral bioavailability. At present, the development of dosage forms with poorly water-soluble active pharmaceutical ingredients (APIs) by means of amorphous solid dispersions (ASDs) approach has been an active area of research. Meanwhile, dielectric heating, a process in which a radio frequency (RF), radio wave or microwave electromagnetic radiation heats materials with dielectric properties, has been applied in the food industry and synthetic organic chemistry for many years. In this work, tablets of indomethacin (IND) ASDs with various polymer matrices were successfully obtained utilizing a novel dielectric heating method on-demand. A series of solid-state analyses, including differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), and polarized light microscopy (PLM) were used for examining drug/polymer miscibility, drug crystallinity and to determine the thermal stability of IND/polymer compositions. In addition, the comparative studies between the amorphous tablets and conventional directly compressed (DC) tablets exhibited higher hardness/compaction results for ASDs tablets (for Soluplus®, HPC HF), but smaller values for the other polymers (HPMC, HPMCAS, E PO, and P EO). The amorphous IND tablets showed improved drug release performance because the polymer matrix stabilized the solution that can maintain a thermodynamic environment for IND. An advanced release mechanism and kinetics study revealed that all ASD tablets exhibited mostly a Fickian diffusion. In contrast, non-cellulose polymer matrices showed swelling, erosion, or both swelling and erosion-controlled drug release. In summary, dielectric heating techniques offer a simple way to manufacture amorphous drug products and presents an alternative solution to the patient to optimize their treatment with conventional dosages.

Towards nanoformulations for skin delivery of poorly soluble API: What does indeed matter?

Loading sparingly soluble active pharmaceutical ingredients (API) and overcoming biological barriers are two challenging issues in the drug delivery and technology fields. In this work, we assessed the influence of composition on the ability of nanosized ethosomes to increase the apparent solubility and drug incorporation, as well as the skin penetration of two hydrophobic drugs, celecoxib and paclitaxel. Ethosomes were produced through the bottom-up method using ethanol injection, and APIs were added in supersaturated ethanolic solution. Variations in the composition of the aqueous phase (containing or not Tween 80 micelles) and phospholipid content (2 or 4%, w/v) were included to assess their effect on ethosomes characteristics and drug apparent solubility. Dynamic light scattering enabled monitoring the non-soluble API precipitation and indicated an increase in size (up to 500–1000 nm) and polydispersity (above 0.3). Soft and fast centrifugation at 5000g for 5 min enabled removal of non-soluble APIs, decreasing size and PDI to ~300–400 nm and 0.2–0.3, respectively. The nanoformulation incorporated ~60–90% of the API added, but short-term stability assays suggested precipitation of paclitaxel at 24–72 h. These results were evaluated by two factorial designs 22, and a significant effect of lecithin concentration on celecoxib solubilization was observed. A tendency of interaction between Tween 80 micelles presence and increased solubilization was observed for celecoxib but not paclitaxel. Higher amounts of celecoxib (~5-fold) were quantified in the stratum corneum and epidermis (minus stratum corneum) + dermis after treatment with ethosomes containing Tween 80 compared to those without the surfactant, but not in the receptor phase. For paclitaxel, presence of Tween 80 micelles did not affect delivery. This work evidenced the feasibility of the ethosomes developed to load poorly water soluble APIs and to deliver them to skin but suggest that this effect vary with composition and the API physicochemical characteristics. Nanocarrier composition and level of molecular complexity and characteristics of APIs are factors that can interact and generate distinctive effects on both API solubilization and delivery to/across the skin.

Feste Lipidnanopartikel zur Applikation unlöslicher Wirkstoffe

Solid lipid nanoparticles are promising carriers to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). While the available amount of API, especially for newly identified substances in pharmaceutical development is often limited, the dual centrifuge ZentriMix 380 R enables the screening of up to 40 formulations at once in very small batches in closed vials within approximately 10 minutes. Due to the included heating facility and the high stress energy induced by grinding media, lipids with melting temperatures of 73 °C could be processed in this study and monomodal formulations with particle sizes of 133 nm were achieved.

Impact of differential particle size of fenofibrate nanosuspensions on biopharmaceutical performance using physiologically based absorption modeling in rats

Particle size and its distribution governs oral biopharmaceutical performance of poorly water-soluble active pharmaceutical ingredients (APIs). Fenofibrate, a poorly water-soluble API, is marketed as both micronized and nanosized formulations having differential biopharmaceutical performance. The present study investigated the impact of differential particle size of fenofibrate (FNT) nanosuspensions on biopharmaceutical performance using physiologically based absorption modeling (PBAM). Nanosuspensions with particle size (D90) of 200–300 nm, 500–600 nm, and 800–1000 nm, coded as B1, B2, and B3, respectively, were generated using media milling. Micronized fenofibrate and Tricor® (nano-sized marketed formulation) were used as controls for the study. Formulations were evaluated for apparent solubility, dissolution, permeability and cellular uptake, while oral bioavailability studies were conducted in Sprague-Dawley rats. PBAM was developed using physicochemical properties and disposition kinetics along fasted-state rat physiology. The model was optimized and used for the prediction of in vivo biopharmaceutical performance of nanosized formulations. The model predicted faster absorption for B1 and Tricor®, which was inconsistent with the observed plasma concentration-time profiles of orally administered formulations in rats. In vitro cellular uptake studies revealed that inconsistency could be due to extended period of absorption with B1 and Tricor®. The latter can be ascribed to (i) mucoadhesion of nanocrystals leading to extended release of FNT and (ii) higher flux and ingress of FNT into enterocyte due to higher apparent solubility of FNT nanocrystals. Once inside enterocytes, FNT rapidly converts to fenofibric acid. It ionizes at cellular pH and gets trapped inside due to poorer permeability of ionized species, which is subsequently absorbed slowly. This phenomenon was incorporated to the model by extending small intestinal transit time and it revealed that the apparent solubilization triggered flux can lead to extension in small intestinal transit time for B1 and Tricor®. The findings from the current study can be useful in the development of bioequivalent nanosuspensions of fenofibrate and PBAM of nanosuspensions for poorly water-soluble APIs.

Vibrational Spectroscopic Investigation into Novel Ternary Eutectic Formed between Pyrazinamide, Fumaric Acid, and Isoniazid.

To improve the efficacy of anti-tuberculosis (anti-TB) therapy, drug–drug co-crystallization stands for an alternative approach to settle the tuberculosis problem. Directly co-crystallizing two typical parent anti-TB drugs (pyrazinamide, PZA and isoniazid, INH) into a single binary co-crystal could not be obtained successfully. Multicomponent eutectic are highly effective and useful for enhancing the dissolution rate, bioavailability, and physical stability of the poorly water-soluble active pharmaceutical ingredient (API) drugs, when the attempts of forming a binary co-crystal have failed. Therefore, the ternary eutectic composition conception was proposed in this study, in which fumaric acid (FA) was chosen as the molecule to connect two first-line anti-tubercular drugs. First of all, three starting materials (including PZA, INH, and FA) were grinded at a 1:1:1 molar ratio, the eutectic composition was investigated through vibrational spectroscopic techniques, including terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. Additionally, the density functional theory (DFT) was utilized to simulate the optimized structures and vibrational modes of two possible theoretical eutectic composition forms. The THz absorption spectrum of the theoretical form I shows much more consistency with the experimental results than that of form II. Raman spectra also help to characterize the differences in vibrational modes between the eutectic composition and the starting parent compounds. The results provide us with both structural information and intermolecular hydrogen bonding interactions within specific multicomponent eutectic composition formulations based on Raman and terahertz vibrational spectroscopic techniques in combination with theoretical calculations.

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances.

Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires® (Gelucire® 50/13 and Gelucire® 48/16 in different ratio) of three BCS class II model compounds (carbamazepine, CBZ, tolbutamide, TBM, and cinnarizine, CIN) having different physicochemical properties (logP, pKa, Tm) were produced by spray congealing process. The obtained MPs were investigated in terms of morphology, particles size, drug content, solid state properties, drug-carrier interactions, solubility, and dissolution performances. The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN. The in vitro tests suggested that the drug solubility was mainly influenced by carrier composition, while the drug dissolution behavior was affected by the API solid state in the MPs after the spray congealing process. Among the tested APIs, TBM-Gelucire dispersions showed the highest enhancement in drug dissolution as a result of the reduced drug crystallinity.

Hydrate formation in polymer-based pharmaceutical formulations

Amorphous solid dispersions (ASD) are state-of-the art enabling formulations for poorly water-soluble active pharmaceutical ingredients (APIs). Depending on the relative humidity (RH), temperature, and API content, ASDs are often metastable against crystallization of the API or even against the formation of API hydrates in the ASD. Knowing the conditions at which API crystals or API hydrate formation may occur in ASDs therefore is an important prerequisite for developing a suitable formulation strategy for APIs. ASDs containing hydrate-forming APIs (carbamazepine/polyvinylpyrrolidone, carbamazepine/hydroxypropylmethylcellulose acetate succinate, and theophylline/polyvinylpyrrolidone) were investigated in this work. The influence of polymer type, RH, API content, and water sorption on the ASD stability was determined via phase diagrams predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These predictions were successfully validated by long-term stability tests at 295 K and 0%, 58%, 76%, 86%, and 93% RH. Hydrate crystals are formed above their critical RH. Thus, ASDs with carbamazepine (critical RH 65% at 295 K) as well as theophylline (critical RH 58% RH) showed hydrate crystals at 76%, 86% and 93% RH, no matter which polymer was used for preparing the ASD.