Dissolution Of Active Pharmaceutical Ingredient Research Articles

A two-stage mechanistic reduced-order model of pharmaceutical tablet dissolution: Population balance modeling and tablet wetting functions

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model’s versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study.

Drug Release and Stability Study of Innovated Losartan Potassium and Rosuvastatin Calcium Fixed-dose Combination Tablet.

Patient adherence to therapy and compliance is always a challenge for care providers in the management of chronic disorders with multiple medications. Our study focused on formulating concurrently prescribed ARB (Angiotensin Receptor Blocker), i.e., losartan potassium, and a cholesterol-lowering statin derivative, i.e., rosuvastatin calcium, in a fixed-dose combination tablet. The drugs were selected based on the presence of synergism and variation in solubility characteristics. Trial batches with fixed concentrations of both active pharmaceutical ingredients (APIs) and varying quantities of different excipients were prepared by dry granulation technique and subjected to different quality control tests for tablets. Batch F5 was selected on the basis of in-process quality control data for the development of a drug release protocol. Experimental conditions were optimized. Based on the sink condition, phosphate buffer (pH 6.8) was selected as the dissolution medium. Simultaneous determination of both APIs in samples collected at predetermined time intervals was carried out using the RP-HPLC technique with acetonitrile, methanol, and water (20:25:55 v/v/v) as mobile phase. Complete dissolution of both APIs in the FDC tablet was achieved in 45 min in 900 mL of the selected medium. The in vitro drug release protocol was validated for accuracy and precision without interference with sample analysis. In this study, a validated, accurate, and robust dissolution testing method was developed for the newly formulated FDC tablet.

Information-Analytical Software for Developing Digital Models of Porous Structures’ Materials Using a Cellular Automata Approach

An information-analytical software has been developed for creating digital models of structures of porous materials. The information-analytical software allows you to select a model that accurately reproduces structures of porous materials—aerogels—creating a digital model by which you can predict their properties. In addition, the software contains models for calculating various properties of aerogels based on their structure, such as pore size distribution and mechanical properties. Models have been implemented that allow the description of various processes in porous structures—hydrodynamics of multicomponent systems, heat and mass transfer processes, dissolution, sorption and desorption. With the models implemented in this software, various digital models for different types of aerogels can be developed. As a comparison parameter, pore size distribution is chosen. Deviation of the calculated pore size distribution curves from the experimental ones does not exceed 15%, which indicates that the obtained digital model corresponds to the experimental sample. The software contains both the existing models that are used for porous structures modeling and the original models that were developed for different studied aerogels and processes, such as the dissolution of active pharmaceutical ingredients and mass transportation in porous media.

Buccal delivery system of active pharmaceutical ingredients-ionic liquid (API-IL): Effects of API-IL loading and gelatin film concentration

Ionic liquid (IL) salt of active pharmaceutical ingredient (API) represents a promising formulation strategy to address low drug solubility and polymorphism prevalent in API solid crystals. The present work developed for the first time a buccal delivery system of API-IL via fast-dissolving API-IL-loaded gelatin films. Imidazolium-based ibuprofen salt was used as the model API-IL. The effects of API-IL loading and gelatin concentration on the film’s (i) mechanical strength, (ii) inter-batch uniformity in the films’ API payload, weight, and thickness, (iii) thermal stability, (iv) API dissolution and solubility enhancement were investigated. The plasticizer role of API-IL was evident, where minimum 30 wt% API-IL loading was needed to produce flexible yet mechanically-strong films. Lower API-IL loading produced brittle films due to insufficient plasticization facilitated by hydrogen bond interactions between API-IL and gelatin. Gelatin concentration influenced films’ mechanical strength, weight/thickness, and API dissolution rate. Depending on the API-IL loading and gelatin concentration, films with API payload (7–30 mg/cm2), thickness (300–900 µm), and weight (20–110 mg/cm2) were produced at nearly 100% efficiency and high inter-batch uniformity. API-IL existed as amorphous liquid in the film exhibiting fast API dissolution (100% in 15 min) and high kinetic solubility (8 times thermodynamic solubility) in simulated saliva fluid.

A novel theoretical strategy for predicting dissolution kinetics and mechanisms of pharmaceuticals in complex biorelevant media

The influence mechanism of biorelevant media on the dissolution of active pharmaceutical ingredients (APIs) is the key to their formulation design. The dissolution kinetics of naproxen (NAP) and indomethacin (IND) in biorelevant media was systematically investigated. The dissolution mechanism was analyzed by chemical potential gradient model to explore the influence of surfactant type, pH and ionic strength. Hexadecyl trimethyl ammonium bromide (CTAB) is superior to sodium dodecyl sulfate (SDS) in promoting the dissolution of NAP and IND by increasing the solubility and accelerating the surface reaction processes. The electrostatic repulsion between SDS and NAP and IND with the same negative charge facilitates the diffusion of API, while the mutual attraction between CTAB and NAP and IND is not conducive to diffusion. High pH was favorable for the dissolution of acidic NAP and IND, as the simultaneous increase in solubility, surface reaction constant, and diffusion constant. High ionic strength was beneficial for the surface reaction of NAP and IND, but hindered their diffusion. It was shown that the modeling results were in conformity with the in vitro experimental data. These results are expected to provide theoretical supports for the design of biorelevant media and pharmaceutical formulations in the pharmaceutical development.

REVIEW PENGARUH PENGGUNAAN SURFAKTAN PADA KARAKTERISTIK SEDIAAN ORODISPERSIBLE FILM (ODF) OBAT BERKELARUTAN RENDAH DALAM AIR: SIFAT DISINTEGRASI DAN DISOLUSI

Orodispersible film (ODF) is a drug delivery gaining widespread acceptance because it disintegrates quickly and can be self-administered. ODF has the advantage of increasing the active pharmaceutical ingredient (API) effectiveness by rapid dissolution in the oral cavity after direct contact with saliva. One of the components of ODF that influences the physical characteristics and dissolution of low-soluble drugs in water is surfactant. This material acts as a wetting or dispersing agent so the film can quickly disintegrate and release API. The method used is searching for international journal data using the Google Scholar. The surfactants reported to have been used in the ODF formulation are L-arginine, poloxamer 407, tween 80, and sodium dodecyl sulfate. In general, surfactant usage significantly affects the disintegration behavior of the film and API release. This behavior is caused by reducing the interfacial tension between phases by surfactants, which causes increased solid surface wetting and helps speed up the film disintegration and API dissolution from the ODF matrix. The conclusion is that surfactant usage with the appropriate type and concentration will help improve the ODF quality, especially in the disintegration properties of the dosage form and API dissolution.

Dissolution of a Biopharmaceutics Classification System Class II Free Acid from Immediate Release Tablets Containing a Microenvironmental pH Modulator: Comparison of a Biorelevant Bicarbonate Buffering System with Phosphate Buffers

Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results—RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators.Graphical abstract

Optimization and troubleshooting of preparative liquid chromatography using statistical design of experiments: Four small-molecule case studies

Statistical design of experiments (DoE) is used to aid in the development and execution of preparative liquid chromatography (LC) for large-scale purification of active pharmaceutical ingredients (API) and pharmaceutical intermediates. Four purification case studies were undertaken. In case study 1, a normal phase preparative silica method is developed and modeled. After initial method screening, DoE results were used to set mobile phase composition, flowrate, and sample diluent. Of the three particle sizes studied (10 µm, 20 µm, 50 µm) only 10 µm silica resin was able to produce purified API at the yield (>96%) and productivity (> 1 kg/kg-resin/day) necessitated by the project. The second case study uses DoE studies to identify critical process parameters of column load, mobile phase solvent ratio and basic modifier level for a low-resolution, preparative, chiral separation. Trade-offs between purity, yield and productivity are quantified in a tight separation which made compromising on process outcomes a necessity. The third case study troubleshoots a loss of yield experienced during operation of a process-scale reverse-phase LC purification. DoE is used to identify a critical interaction between levels of acetonitrile and phosphoric acid in the mobile phase. An operating region which increased yield from around 85% to 97% was defined and implemented. The fourth case study was initially designed as a preparative chromatography purification of API. DoE was used to screen mobile phase solubility. These experiments uncovered conditions where API is soluble, and impurities are not. The solubility model in acetonitrile/water mixtures is further defined via a response surface DoE. The resulting targeted solvent mixture allows bulk purification via dissolution of API while three less-polar impurities remain in the solid phase and are removed by filtration. These four case studies demonstrate the efficiency of DoE and response surface modeling as tools for process development and optimization.

The impact of the lamination pressure on the properties of electrospinned nanofibrous films

The purpose of this work is to explore the preparation of nanofibrous orally dispersible films (ODFs) by needleless electrospinning from the active pharmaceutical ingredient (API) Tadalafil using particles suspended in a solution of polymers and other excipients. The prepared films were characterized by a combination of scanning electron microscopy, mechanical tests, measurements of the disintegration time and dissolution characteristic, X-ray diffraction, and differential scanning calorimetry. Furthermore, we investigated the impact of lamination pressures in the range of 0 to 5 bars combined with films at various relative humidity values on the mechanical properties of the ODF. An increase in lamination pressure resulted in higher Young's modulus values, with the maximum value observed for a sample laminated at a pressure of 5 bar and the maximum stress and strain of the prepared ODF at a lamination pressure of 1.2 bar. Moreover, there was a significant increase in the disintegration time with increase in lamination pressure. The disintegration time ranged from 0.35 s for non-laminated samples to 12 s for samples laminated at a pressure of 5 bar. On the contrary, the lamination pressure did not reveal to have any impact on the dissolution kinetics. These results confirmed that the lamination pressure can improve the processability of ODFs without affecting the API dissolution kinetics.

DESIGN OF DISSOLUTION STUDY PROTOCOL FOR PULMONARY DOSAGE FORMS: CRITERIA FOR SELECTION OF BIO-RELEVANT DISSOLUTION MEDIUM

Pulmonary dosage forms constitute an important route of drug delivery for systemic absorption of drugs in management of respiratory diseases as well as diseases such as diabetes, migraine, osteoporosis, and cancer. Performance of different pulmonary dosage forms is greatly influenced by aerodynamic particle size distribution of inhalable particles, spray pattern, fraction of dose actually deposited on pulmonary epithelium, dissolution of active pharmaceutical ingredient and ultimately absorption across pulmonary barriers. In vitro dissolution study should be designed to predict in vivo performance precisely, providing key information on bioavailability and establishing in vitro-in vivo correlation. To obtain meaningful data from dissolution study, focus should be on composition of dissolution medium, dissolution conditions and dissolution test apparatus. For pulmonary dosage forms, selection of physiologically relevant dissolution medium, mimicking lung fluid (LF) is a challenging task. Attempts are being made to develop bio-relevant dissolution medium to overcome the limitations associated with use of conventional media lacking lung surfactant proteins, or several salts normally present in pleural fluid. Use of simulated LFs can give a better understanding of the release mechanisms and possible in vivo behavior of pulmonary dosage forms thereby enhancing the predictive capability of the dissolution testing. In the review, efforts have been taken to provide comprehensive information on composition, physicochemical characteristics and functions of physiological LF, challenges associated with the design and development of dissolution study protocol for pulmonary dosage forms, criteria for selection of an appropriate bio-relevant dissolution medium, comparative study on various reported bio-relevant dissolution media and dissolution apparatuses employed for in vitro characterization of performance of pulmonary dosage forms.

Nanoconfinement of a Pharmaceutical Cocrystal with Praziquantel in Mesoporous Silica: The Influence of the Solid Form on Dissolution Enhancement.

Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this work, we combine the advantage of cocrystals of racemic praziquantel (PZQ) containing a water-soluble coformer (i.e., increased solubility and supersaturation) and its confinement in a mesoporous silica material (i.e., increased dissolution rate). Among various potential cocrystalline phases of PZQ with dicarboxylic acid coformers, the cocrystal with glutaric acid (PZQ-GLU) was selected and successfully loaded by the melting method into nanopores of SBA-15 (experimental pore size of 5.6 nm) as suggested by physical and spectroscopic characterization using various complementary techniques like N2 adsorption, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), solid-state NMR (ss-NMR), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM) analysis. The PZQ-GLU phase confined in SBA-15 presents more mobility according to ss-NMR studies but still retains its cocrystal-like features in the IR spectra, and it also shows depression of the melting transition temperature in DSC. On the contrary, pristine PZQ loaded into SBA-15 was found only in the amorphous state, according to the aforementioned studies. This dissimilar behavior of the composites was attributed to the larger crystal lattice of PZQ over the PZQ-GLU cocrystal (3320.1 vs 1167.9 Å3) and to stronger intermolecular interactions between PZQ and GLU, facilitating the confinement of a more mobile solid-like phase in the constrained channels. Powder dissolution studies under extremely nonsink conditions (SI = 0.014) of the confined PZQ-GLU and amorphous PZQ phases embedded in mesoporous silica showed transient supersaturation behavior when dissolving in simulated gastric fluid (HCl pH 1.2 at 37 ± 0.5 °C) in a similar fashion to the bare cocrystal PZQ-GLU. A comparison of the area under the curve (AUC0-90min) of the dissolution profiles afforded a dissolution advantage of 2-fold (p < 0.05) of the new solid phases over pristine racemic PZQ after 90 min; under these conditions, the solubilized API reprecipitated as the recently discovered PZQ hemihydrate (PZQ-HH). In the presence of a cellulosic polymer, sustained solubilization of PZQ from composites SBA-15/PZQ or SBA-15/PZQ-GLU was observed, increasing AUC0-90min up to 5.1-fold in comparison to pristine PZQ. The combination of a confined solid phase in mesoporous silica and a methylcellulose polymer in the dissolution medium effectively maintained the drug solubilized during times significant to promote absorption. Finally, powder dissolution studies under intermediate nonsink conditions (SI = 1.99) showed a fast release profile from the nanoconfined PZQ-GLU phase in SBA-15, which reached rapid saturation (95% drug dissolved at 30 min); the amorphous PZQ composite and bare PZQ-GLU also displayed an immediate release of the API but at a lower rate (69% drug dissolved at 30 min). In all of these cases, a large dissolution advantage was observed from any of the novel solid phases over PZQ.

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.

Kinetics of neomycin release from polylactide spheres and its antimicrobial activity.

Neomycin is a natural aminoglycoside antibiotic produced by actinomycete Streptomyces fradiae. It exerts bacteriostatic and bactericidal activity against Gram-negative bacteria, certain Gram-positive bacteria and Mycobacterium tuberculosis. Neomycin inhibits the biosynthesis of bacterial proteins by impairing their life functions, leading to death of cells. To examine the effect of molecular weight of polylactide (PLA), the applied stabilizer as well as mixing speed used in the encapsulation process on the size of obtained spheres. Examination of the kinetics of neomycin release from the obtained PLA spheres and determination of the antimicrobial activity of the neomycin-containing spheres against selected strains of bacteria, yeast and fungi have also been necessary. Polylactide (Mn 3000-40,000 g/mol) was obtained in-house. Other materials used in the study were as follows: L-lactic acid (PLLA; Mn 66,500 g/mol and 86,000 g/mol), polyvinyl alcohol (PVA) as a stabilizer of emulsion (Mw 30,000 g/mol, 130,000 g/mol; degree of hydrolysis 88%) as well as dichloromethane, p.a. and dimethyl sulfoxide (DMSO), p.a. as solvents. Distilled water was obtained in-house. Neomycin sulfate was used for encapsulation; phosphate (pH 7.2) and acetate (pH 4.5) buffers were used for the examination of the active pharmaceutical ingredient (API) dissolution profile. Antimicrobial activity was tested using commercial cell lines and the following media: Mueller-Hinton agar (MHA), Mueller-Hinton broth (MHB), yeast extract peptone dextrose (YPD), and potato dextrose agar (PDA). Neomycin-containing PLA spheres were obtained using an emulsion method. The average molecular weight of PLA, the average molecular weight of PVA and mixing speed on the size of obtained spheres were investigated. Furthermore, the profile of API dissolution from the spheres and antimicrobial activity of neomycin-containing spheres against certain strains of bacteria, yeast and fungi were determined. We demonstrated that efficient encapsulation of neomycin requires spheres of a <200 mm diameter.

A Systematic Approach in the Development of the Morphologically-Directed Raman Spectroscopy Methodology for Characterizing Nasal Suspension Drug Products

Demonstrating bioequivalence (BE) of nasal suspension sprays is a challenging task. Analytical tools are required to determine the particle size of the active pharmaceutical ingredient (API) and the structure of a relatively complex formulation. This study investigated the utility of the morphologically-directed Raman spectroscopy (MDRS) method to investigate the particle size distribution (PSD) of nasal suspensions. Dissolution was also investigated as an orthogonal technique. Nasal suspension formulations containing different PSD of mometasone furoate monohydrate (MFM) were manufactured. The PSD of the MFM batches was characterized before formulation manufacture using laser diffraction and automated imaging. Upon formulation manufacture, the droplet size, single actuation content, spray pattern, plume geometry, the API dissolution rate, and the API PSD by MDRS were determined. A systematic approach was utilized to develop a robust method for the analysis of the PSD of MFM in Nasonex® and four test formulations containing the MFM API with different particle size specifications. Although the PSD between distinct techniques cannot be directly compared due to inherent differences between these methodologies, the same trend is observed for three out of the four batches. Dissolution analysis confirmed the trend observed by MDRS in terms of PSD. For suspension-based nasal products, MDRS allows the measurement of API PSD which is critical for BE assessment. This approach has been approved for use in lieu of a comparative clinical endpoint BE study [1]. The correlation observed between PSD and dissolution rate extends the use of dissolution as a critical analytical tool demonstrating BE between test and reference products.

Exploring the Role of Anti-solvent Effects during Washing on Active Pharmaceutical Ingredient Purity.

Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.

Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid-Sulfamethazine Cocrystals.

Drug–drug cocrystals are formulated to produce combined medication, not just to modulate active pharmaceutical ingredient (API) properties. Nano-crystals adjust the pharmacokinetic properties and enhance the dissolution of APIs. Nano-cocrystals seem to enhance API properties by combining the benefits of both technologies. Despite the promising opportunities of nano-sized cocrystals, the research at the interface of nano-technology and cocrystals has, however, been described to be in its infancy. In this study, high-pressure homogenization (HPH) and high-power ultrasound were used to prepare nano-sized cocrystals of 4-aminosalysilic acid and sulfamethazine in order to establish differences between the two methods in terms of cocrystal size, morphology, polymorphic form, and dissolution rate enhancement. It was found that both methods resulted in the formation of form I cocrystals with a high degree of crystallinity. HPH yielded nano-sized cocrystals, while those prepared by high-power ultrasound were in the micro-size range. Furthermore, HPH produced smaller-size cocrystals with a narrow size distribution when a higher pressure was used. Cocrystals appeared to be needle-like when prepared by HPH compared to those prepared by high-power ultrasound, which had a different morphology. The highest dissolution enhancement was observed in cocrystals prepared by HPH; however, both micro- and nano-sized cocrystals enhanced the dissolution of sulfamethazine.

Investigation of Poor Solubility of a Salt-Cocrystal Hydrate: A Case Study of the Common-Ion Effect in Betrixaban, an Anticoagulant Drug.

Achieving the desired solubility and dissolution of active pharmaceutical ingredients (APIs) continues to be a big challenge in the pharmaceutical industry. In this regard, multicomponent solids of APIs such as salts and cocrystals have shown significant promise in resolving such solubility/dissolution issues. However, very little is known on how the APIs' solubility or dissolution is affected by the drug to coformer ratio in multicomponent solids. Betrixaban, is an anticoagulant drug approved in 2017 for the prevention of venous thromboembolism. During the alternate solid form development studies of the known betrixaban maleate, a rare multicomponent solid form, salt-cocrystal hydrate of betrixaban, was discovered and characterized thoroughly by spectroscopic, thermal, and X-ray crystallographic methods. Significantly, the new betrixaban maleate maleic acid hydrate (1:1:2:1) form has shown lower melting point (80 °C) as compared to its parent salt (197.5 °C). From such a large melting difference (117 °C) between the salt and salt-cocrystal hydrate of API, we anticipated substantially better solubility for the salt-cocrystal hydrate (low enthalpy). Furthermore, the predicted solubility also supported our anticipation. However, the powder dissolution tests at different pH conditions provided contrary results, that is, the salt-cocrystal hydrate showed 10 times lower solubility as compared to its salt. A detailed investigation, considering all the potential factors, revealed that "common-ion effect" could be a critical factor for the low solubility of the salt-cocrystal hydrate in which the API to coformer ratio is 1:3. To the best of our knowledge, this is the first case study on the solubility of pharmaceutical salt-cocrystal hydrates with an emphasis on "common-ion effect" or drug to coformer ratio.

An improved method for the simultaneous determination of water uptake and swelling of tablets

Water uptake and swelling of tablets are processes occurring during active pharmaceutical ingredient (API) release. Thereby, disintegration is promoted and the enhanced exposure of API surface area to the release medium facilitates API dissolution. An experimental set-up for the simultaneous and time-resolved determination of water uptake and swelling of tablets has been developed. Water uptake was determined with a balance and swelling was determined with a camera. To validate the gravimetrical analysis, real-time water uptake measurements with inert test specimens were performed. The standard deviation of these measurements was considered to depict precision. A complementary gravimetrical analysis was employed to determine accuracy. For both, precision and accuracy, a maximum deviation of 6% was found. An algorithm for the symmetry-based 3D volume reconstruction was applied to obtain volumes of the tablets from 2D images. X-ray micro computed tomography was used to validate the accuracy and the determined volumes were in good accordance within 6% deviation. A case study with binary formulations of a filler and disintegrants confirmed reproducibility and demonstrated the ability of the method to discriminate formulation characteristics, such as disintegrant type, composition and porosity for water uptake and swelling with the necessary temporal resolution.

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.

Pharmaceutical Properties of Anti-inflammatory Analgesic Patches Using Acrylic Polymer

The mock patches were prepared with novel acrylic polymers as adhesive layer where biphenyl-4-ylacetic acid (BAA) or 2-(2-fluorobiphenyl-4-yl) propanoic acid (FPA) was used as model active pharmaceutical ingredients (APIs). In addition, the mock patches were formulated with typical ester ingredients for transdermal dosage forms. The molecular state of the model APIs in the adhesive layer was observed by polarized microscope and microscopic Raman spectroscopy, which contains both conventional and low frequency (LF) region. Crystallization behavior would be depended on the interaction between API and polymers in the adhesive layer. In particular, LF Raman measurement was useful to discriminate API polymorphs. The pharmaceutical properties including dissolution and skin permeation of APIs were also evaluated for mock patches. The drug release and transdermal permeation were enhanced with the ester ingredients such as isopropyl myristate and diethyl sebacate due to their diffusion to the test solution or the skin stratum corneum as well as reducing the interaction between API and polymers. Further, the tack strength was not changed, but the peel strength was weakened by the additives. Thus, the adhesive properties were controllable by formulation with the additives. These findings could enable to evaluate the interaction between API and the polymers for adhesive layer and select the appropriate polymer and additives for used APIs when designing the drug products.