Insights into the Mechanism of Enhanced Dissolution in Solid Crystalline Formulations.

Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier- and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.

[Advantage analysis of flow-through cell method in quality evaluation of Chinese patent medicine: a case study of Danshen Tablets].

To explore the quality consistency evaluation method for multi-component traditional Chinese medicine and establish a dissolution evaluation method suitable for the characteristics of multi-component Chinese patent medicine, this study discussed the characteristics and advantages of the flow-through cell method in the dissolution evaluation of Chinese patent medicine by comparing the impact of the small cup method and the flow-through cell method on the dissolution behavior of water-soluble and lipid-soluble major active components of Danshen Tablets. Dissolution tests were performed using the small cup method as described in the 2020 edition of the Chinese Pharmacopoeia and the newly introduced flow-through cell method(closed-loop method) with water solution containing 0.5% SDS as dissolution medium. Cumulative dissolution curves of the water-soluble component salvianolic acid B and the lipid-soluble component tanshinone Ⅱ_A in Danshen Tablets were plotted, and fitting and similarity analysis of the dissolution models was conducted to identify the characteristics and advantages of the flow-through cell method. For the small cup method, 150 mL of water containing 0.5% SDS was used as the dissolution medium, with a rotation speed of 75 r·min~(-1) and a temperature of(37±0.5) ℃, and 3 mL of samples were taken at 15, 30 min, 1, 2, and 4 h, with fresh dissolution medium added at the same temperature and volume. For the flow-through cell method, a closed-loop system was used. Danshen Tablets were placed in the flow-through cell with approximately 6.7 g of glass beads, and 150 mL of water containing 0.5% SDS was used as the dissolution medium. The flow rate was set at 20 mL·min~(-1), and the temperature and sampling were the same as the small cup method. The results showed that compared with the small cup method, the flow-through cell method had stronger discriminative power and higher sensitivity in distinguishing the dissolution behavior of the two components, and could better reflect the differences in formulation quality, especially for water-insoluble lipid-soluble components. Given that there were no essential differences in the in vitro release kinetics between the two methods, the flow-through cell method could not only replace the traditional small cup method but also better guide the formulation development and identify quality issues of formulations.

Optical glucose sensor for microfluidic cell culture systems.

Glucose is the primary energy source of human cells. Therefore, monitoring glucose inside microphysiological systems (MPS) provides valuable information on the viability and metabolic state of the cultured cells. However, continuous glucose monitoring inside MPS is challenging due to a lack of suitable miniaturized sensors. Here we present an enzymatic, optical glucose sensor element for measurement inside microfluidic systems. The miniaturized glucose sensor (Ø 1 mm) is fabricated together with a reference oxygen sensor onto biocompatible, pressure-sensitive adhesive tape for easy integration inside microfluidic systems. Furthermore, the proposed microfluidic system can be used as plug and play sensor system with existing MPS. It was characterized under cell culture conditions (37 °C and pH 7.4) for five days, exhibiting minor drift (3% day-1). The influence of further cell culture parameters like oxygen concentration, pH, flow rate, and sterilization methods was investigated. The plug-and-play system was used for at-line measurements of glucose levels in (static) cell culture and achieved good agreement with a commercially available glucose sensor. In conclusion, we developed an optical glucose sensor element that can be easily integrated in microfluidic systems and is able to perform stable glucose measurements under cell culture conditions.

PhysioCell®; - a Novel, Bio-relevant Dissolution Apparatus: Hydrodynamic Conditions and Factors Influencing the Dissolution Dynamics.

The physiologically relevant dissolution apparatuses simulate various aspects of gastrointestinal physiology and help to understand and predict the in vivo behavior of an oral dosage form. In this paper, we present and characterize for the first time a novel bio-relevant dissolution apparatus - PhysioCell®;. We evaluated the impact of several factors on the hydrodynamic conditions in the key vessel of the apparatus - the StressCell. We observed that the medium flow rate, but not the glass beads' size or amount, significantly influenced the dissolution rate. The relationship was disproportional: the increase in the flow rate from 4.6 to 9.0 mL/min reduced the dissolution time of 85% (T85) of the NaCl tablet by 46%, but from 134 to 300 mL/min decreased the T85 only by 24%. At the same time, the contractions of the StressCell's elastic walls promoted the content mixing and enhanced the dissolution rate of the paracetamol tablets: even very rare mixing contractions (1 per 10 min) decreased the T85 over twofold for the flow rate of 8 mL/min. In conclusion, the hydrodynamic conditions in the StressCell affect the dissolution of solid dosage forms and the understanding of these effects is crucial for modeling physiologically-based test conditions in the novel apparatus. Combinations of the unique PhysioCell®;features - adjustable medium flow, temperature control, controllable pH gradients and predefined mechanical agitation - can create a set of dissolution test scenarios for characterization of oral dosage forms and, in the future, making the in vitro-in vivo predictions. Graphical Abstract.

Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets.

The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bicarbonate buffer solution (pH 5.5-7.5; 5-50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4-8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ∆pH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.

Direct electrochemical determination of environmentally harmful pharmaceutical ciprofloxacin in 3D printed flow-through cell.

Rising amounts of antibiotic residues in wastewater cause serious problems including increased bacterial resistance. Wastewater treatment plants (WWTPs) do not, in the case of new, modern pharmaceuticals, ensure their complete removal. Ciprofloxacin (CIP) is one of many micropollutants that partially pass through WWTPs, implying that its monitoring is essential for the assessment of the water quality. In real sewage systems, the determination of CIP needs to be performed under flowing conditions, which calls for the deployment of inexpensive, robust, and easily integrable approaches such as electrochemical techniques. However, to the best of our knowledge, there is no report on the electrochemical determination of CIP in a flowing matrix. To bridge this gap, we perform here cyclic and square-wave voltammetric sensing study of CIP employing boron-doped diamond screen printed electrodes in a custom-made 3D printed flow-through cell to mimic conditions in real sewage systems. An irreversible two-step oxidation of CIP is demonstrated, with the first step providing clear Faradaic response as analytically relevant signal. This response was found to scale with the sample flow rate according to the prediction given by Levich equation. Our work provides an in-depth inspection of the electrochemical response of CIP under controlled-convection conditions, which is an essential prerequisite for monitoring this antibiotic in real flowing sewage systems.

Advantage analysis of flow-through cell method in quality evaluation of Chinese patent medicine: a case study of Danshen Tablets / 中国中药杂志

To explore the quality consistency evaluation method for multi-component traditional Chinese medicine and establish a dissolution evaluation method suitable for the characteristics of multi-component Chinese patent medicine, this study discussed the characteristics and advantages of the flow-through cell method in the dissolution evaluation of Chinese patent medicine by comparing the impact of the small cup method and the flow-through cell method on the dissolution behavior of water-soluble and lipid-soluble major active components of Danshen Tablets. Dissolution tests were performed using the small cup method as described in the 2020 edition of the Chinese Pharmacopoeia and the newly introduced flow-through cell method(closed-loop method) with water solution containing 0.5% SDS as dissolution medium. Cumulative dissolution curves of the water-soluble component salvianolic acid B and the lipid-soluble component tanshinone Ⅱ_A in Danshen Tablets were plotted, and fitting and similarity analysis of the dissolution models was conducted to identify the characteristics and advantages of the flow-through cell method. For the small cup method, 150 mL of water containing 0.5% SDS was used as the dissolution medium, with a rotation speed of 75 r·min~(-1) and a temperature of(37±0.5) ℃, and 3 mL of samples were taken at 15, 30 min, 1, 2, and 4 h, with fresh dissolution medium added at the same temperature and volume. For the flow-through cell method, a closed-loop system was used. Danshen Tablets were placed in the flow-through cell with approximately 6.7 g of glass beads, and 150 mL of water containing 0.5% SDS was used as the dissolution medium. The flow rate was set at 20 mL·min~(-1), and the temperature and sampling were the same as the small cup method. The results showed that compared with the small cup method, the flow-through cell method had stronger discriminative power and higher sensitivity in distinguishing the dissolution behavior of the two components, and could better reflect the differences in formulation quality, especially for water-insoluble lipid-soluble components. Given that there were no essential differences in the in vitro release kinetics between the two methods, the flow-through cell method could not only replace the traditional small cup method but also better guide the formulation development and identify quality issues of formulations.

Development of Flow-Through Cell Dissolution Method for In Situ Visualization of Dissolution Processes in Solid Dosage Forms Using X-ray µCT.

Visualization of the dynamic behavior of pharmaceutical dosage forms during the dissolution process offers a better understanding of the drug release mechanism, enabling the design of customized dosage forms. In this study, an X-ray tomography-based approach is proposed to monitor and analyze the dynamics of the structure at the pore scale level during the dissolution process. A flow-through cell dissolution apparatus was developed, capable of mimicking the standard in vitro dissolution process, which can be easily positioned in an X-ray tomography setup. The method was utilized to study the dissolution of a Capa® (polycaprolactone)-based sustained-release 3D printed tablet. The impact of the flow rate on the active pharmaceutical ingredient (API) release rate was studied and 16 mL/min was selected as a suitable flow rate. Furthermore, cesium chloride (CsCl) was used as a contrast agent to increase the contrast between the sample and the dissolution medium. Data obtained with this novel technique were in a good agreement with the released drug rate acquired by the standard in vitro dissolution test (the similarity factor (f2) = 77%). Finally, the proposed approach allowed visualizing the internal structure of the sample, as well as real-time tracking of solution ingress into the product.

Convolution- and Deconvolution-Based Approaches for Prediction of Pharmacokinetic Parameters of Diltiazem Extended-Release Products in Flow-Through Cell Dissolution Tester.

The present study evaluated the effect of different configuration setups of the Flow-Through Cell (USP IV) dissolution tester in developing in vitro-in vivo correlation (IVIVC). A Biopharmaceutics Classification System (BCS) Class I Diltiazem (DTZ), formulated in extended-release (ER) gel-matrix system, was employed for this purpose. The study also assessed the validity and predictability of IVIVC employing both deconvolution- and convolution-based approaches. In vitro release was conducted in USP IV as open- or closed-loop setups, while the pharmacokinetic (PK) data were obtained from a previous fasted-state cross-over study conducted on 8 healthy male volunteers, after oral administration of ER matrix tablets against market product (Tildiem Retard® 90 mg). PK parameters (Cmax, AUC0-t and AUC0-∞) were predicted, and compared with actual data to establish the strength of correlation models. Results showed that DTZ release from ER products was influenced by operating the FTC in different configuration-setups, where ≥ 75% of labeled DTZ was released after 6 h and 12 h using the open- and closed-loop settings, respectively. Correlation between fraction-dissolved versus fraction-absorbed for both ER products displayed linear relation upon employing FTC open-loop setup. Convolution-based approach was more discriminative in predicting DTZ in vivo PK parameters with a minimal prediction error, compared to deconvolution-based approach. A successful trial to predict DTZ PKs from individual in vitro data performed in USP IV dissolution model was established, employing convolution technique. Basic principle of the convolution approach provides a simple and practical method for developing IVIVC, hence could be utilized for other BCS Class I extended-release drug products.

Development of a Novel Gastric Process Simulation Model: The Successful Assessment of Bioequivalence and Bioinequivalence of a Biopharmaceutics Classification System Class II Weak Acid Drug.

Bioequivalence has been assessed using in vitro dissolution testing, such as in vivo predictive dissolution methodology. However, the assessment of bioequivalence should be performed carefully, considering the effect of the in vivo environment and according to the properties of the drug. The gastric emptying process is a key factor for the assessment of biopharmaceutics classification system class II (BCS class IIa) drugs with acidic properties since they cannot dissolve in the acidic stomach, but do dissolve in the small intestine (SI). The disintegration of a tablet in the stomach affects the distribution/dissolution in the SI due to the difference in the gastric emptying step, which in turn is a result of the varying formulation of the drugs. In this study, we used the reported dynamic pH change method and a novel gastric process simulation (GPS) model, which can compare the gastric emptying of particular-sized drug particles. The in vitro results were compared to clinical data using bioequivalent and bioinequivalent products of candesartan cilexetil. It was revealed that the dynamic pH change method was inappropriate, whereas the amount of filtered drug in GPS studies with 20 and 50 µm pore size filters could reflect the clinical results of all products. The evaluation of the gastric emptying process of drug particles less than 50 µm enabled us to assess the bioequivalence because they probably caused the difference in the distribution in the SI. This study demonstrated the utility of the GPS model for the assessment of bioequivalence of BCS class IIa drugs.

Altered Media Flow and Tablet Position as Factors of How Air Bubbles Affect Dissolution of Disintegrating and Non-disintegrating Tablets Using a USP 4 Flow-Through Cell Apparatus.

This study investigated how air bubbles in media affect tablet dissolution in a flow-through cell system (USP 4) using disintegrating (USP prednisone) and non-disintegrating (USP salicylic acid) tablets. Cell hydrodynamics were studied using particle image velocimetry (PIV) and computational fluid dynamics (CFD). The PIV analysis showed periodic changes in the local flow corresponding to the discharge and suction of the pump cycles. The absence of prior deaeration induced small air bubbles in the media and lower maximum flow during the cycle, explaining the slower dissolution of the USP salicylic acid tablets. Bubbles, occurring during the USP prednisone tablets study, induced the transition of floating disintegrated particles towards the cell outlet, whereas the particles precipitated to form a white layer on the glass beads used in the study with prior deaeration. CFD analysis showed local flow variation in multiple positions of small (ID 12 mm) and large (ID 22.6 mm) cells, explaining the different rates of dissolution of prednisone tablet particles depending on their distribution. These results emphasize the importance of prior deaeration in dissolution studies using a flow-through system. Bubbles in the flow-through cell system affected tablet dissolution by reducing the area in contact with the media (wettability), lowering the maximum instantaneous flow (pressure buffering), and altering the position of disintegrated particles in the cell.

One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products.

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo-Riegelman method. Time scaling with Levy's plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.

Characterization, in vitro dissolution, and pharmacokinetics of different batches of efavirenz raw materials.

OBJECTIVE: To perform the solid-state characterization and the in vitro-in vivo correlation (IVIVC) of three batches of efavirenz (EFV) active pharmaceutical ingredients. SIGNIFICANCE: EFV is an effective anti-HIV drug. Due to the poor aqueous solubility, the rate and extent of EFV absorption deeply depend on its dissolution characteristics. METHODS: Thermal analyses, x-ray diffraction, and particle size distribution were performed. The saturation solubility and dissolution profiles were assessed in 0.5% (w/v) sodium lauryl sulfate (SLS), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) using a flow-through cell. Each batch was orally administered to Wistar rats and the pharmacokinetic parameters were correlated with those obtained from in vitro dissolution. RESULTS: All batches of EFV consisted polymorph I. EFV-A presented the lowest particle size distribution [d(v,0.5) = 197.8 µm; d(v,0.9) = 444.6 µm] followed by EFV-B [d(v,0.5) = 223.9 µm; d(v,0.9) = 481.1 µm], and EFV-C [d(v,0.5) = 240.8 µm; d(v,0.9) = 497.3 µm]. The saturated solubility in FaSSIF was 36% and 40% of that in FeSSIF and SLS, respectively. EFV-A presented the fastest rate and largest extension of dissolution than EFV-B and C (79.15%, 69.93% and 54.22%, respectively, as well as the highest maximum plasma concentration. Levels B, C, and multiple-C of IVIVC models were achieved. CONCLUSION: The FaSSIF medium discriminated the dissolution profiles of EFV APIs. Small differences in particle size distribution had a significant impact on the biopharmaceutical parameters of EFV, suggesting that strict control of such parameter is an important aspect during API development and drug formulation.

Automated Electrochemical Glucose Biosensor Platform as an Efficient Tool Toward On-Line Fermentation Monitoring: Novel Application Approaches and Insights.

Monitoring and control of fermentation processes remain a crucial challenge for both laboratory and industrial-scale experiments. Reliable identification and quantification of the key process parameters in on-line mode allow operation of the fermentation at optimal reactor efficiency, maximizing productivity while minimizing waste. However, state-of-the-art fermentation on-line monitoring is still limited to a number of standard measurements such as pH, temperature and dissolved oxygen, as well as off-gas analysis as an advanced possibility. Despite the availability of commercial biosensor-based platforms that have been established for continuous monitoring of glucose and various biological variables within healthcare, on-line glucose quantification in fermentation processes has not been implemented yet to a large degree. For the first time, this work presents a complete study of a commercial flow-through-cell with integrated electrochemical glucose biosensors (1st generation) applied in different media, and importantly, at- and on-line during a yeast fed-batch fermentation process. Remarkably, the glucose biosensor-based platform combined with the developed methodology was able to detect glucose concentrations up to 150 mM in the complex fermentation broth, on both cell-free and cell-containing samples, when not compromised by oxygen limitations. This is four to six-fold higher than previously described in the literature presenting the application of biosensors predominately toward cell-free fermentation samples. The automated biosensor platform allowed reliable glucose quantification in a significantly less resource and time (<5 min) consuming manner compared to conventional HPLC analysis with a refractive index (RI) detector performed as reference measurement. Moreover, the presented biosensor platform demonstrated outstanding mechanical stability in direct contact with the fermentation medium and accurate glucose quantification in the presence of various electroactive species. Coupled with the developed methodology it can be readily considered as a simple, robust, accurate and inexpensive tool for real-time glucose monitoring in fermentation processes.

In Vitro-In Vivo Correlation for Solid Dispersion of a Poorly Water-Soluble Drug Efonidipine Hydrochloride.

The aim of this present study was to investigate the ability of different dissolution methods to predict the in vivo performance of efonidipine hydrochloride (EFH). The solid dispersions of EFH were prepared by solvent evaporation method with HPMC-AS as matrix and urea as a pH adjusting agent. The paddle method, the open-loop, and the closed-loop flow-through cell methods were studied. In the study, Weibull's model was the best fit to explain release profiles. The pharmacokinetics behaviors of two kinds of solid dispersions with different release rate were investigated in comparison to the EFH after oral administration in rats. In vivo absorption was calculated by a numerical deconvolution method. In the study, the level A in vivo and in vitro correlation (IVIVC) was utilized. The correlation coefficient was calculated and interpreted by means of linear regression analysis (Origin.Pro.8.5 software). As a result, excellent IVIVC for solid dispersions and crude drug (r2 = 0.9352-0.9916) was obtained for the dissolution rate determined with flow-through cell open-loop system in phosphate buffer solution with 0.1% (w/v) polysorbate 80 at pH 6.5, the flow-rate of 4 mL/min. In addition, the self-assembled flow cell system had good repeatability and accuracy. The dissolution rate of the solid dispersion could be slowed down by the flow-through method, and the difference caused by preparation was significantly distinguished. The study demonstrated that flow-through cell method of the open-loop, compared with paddle method, was suitable for predicting in vivo performance of EFH solid dispersions.

Direct Drug Analysis in Polymeric Implants Using Desorption Electrospray Ionization - Mass Spectrometry Imaging (DESI-MSI).

PURPOSE: Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) coupled with gas-phase ion mobility spectrometry was used to characterize the drug distribution in polymeric implants before and after exposure to accelerated in vitro release (IVR) media. DESI-MSI provides definitive chemical identification and localization of formulation components, including 2D chemical mapping of individual components with essentially no sample preparation. METHODS: Polymeric implants containing 40% (w/w) entecavir and poly(D,L-lactide) (PLA) were prepared and then exposed to either acidified PBS (pH 2.5) or MeOH:H2O (50:50, v/v) medias during a 7-day IVR test using continuous flow-through (CFT) cell dissolution. The amount of drug released from the polymer matrix during the 7-day IVR test was monitored by online-ultraviolet spectroscopy (UV) and HPLC-UV. After that period, intact implants and radial sections of implants were analyzed by DESI-MSI with ion mobility spectrometry. The active ingredient along with impurities and contaminants were used to generate chemical maps before and after exposure to the release medias. RESULTS: Bi-phasic release profiles were observed for implants during IVR release using both medias. During the second phase of release, implants exposed to PBS, pH 2.5, released the entecavir faster than the implants exposed to MeOH:H2O (50:50, v/v). Radial images of the polymer interior show that entecavir is localized along the central core of the implant after exposure to MeOH:H2O (50:50, v/v) and that the drug is more uniformly distributed throughout the implant after exposure to acidified PBS (pH 2.5). CONCLUSIONS: DESI-MSI coupled with ion mobility analysis produced chemical images of the drug distribution on the exterior and interior of cylindrical polymeric implants before and after exposure to various release medias. These results demonstrated the utility of this technique for rapid characterization of drug and impurity/degradant distribution within polymeric implants with direct implications for formulation development as well as analytical method development activities for various solid parenteral and oral dosage forms. These results are especially meaningful since samples were analyzed with essentially no preparative procedures.

Interpreting In Vitro Release Performance from Long-Acting Parenteral Nanosuspensions Using USP-4 Dissolution and Spectroscopic Techniques.

Injectable sustained release dosage forms have emerged as desirable therapeutic routes for patients that require life-long treatments. The prevalence of drug molecules with low aqueous solubility and bioavailability has added momentum toward the development of suspension-based long-acting parenteral (LAP) formulations; the previously undesirable physicochemical properties of Biopharmaceutics Classification System (BCS) Class II/IV compounds are best suited for extended release applications. Effective in vitro release (IVR) testing of crystalline suspensions affirms product quality during early-stage development and provides connections with in vivo performance. However, before in vitro-in vivo correlations (IVIVCs) can be established, it is necessary to evaluate formulation attributes that directly affect IVR properties. In this work, a series of crystalline LAP nanosuspensions were formulated with different stabilizing polymers and applied to a continuous flow-through (USP-4) dissolution method. This technique confirmed the role of salt effects on the stability of polymer-coated nanoparticles through the detection of disparate active pharmaceutical ingredient (API) release profiles. The polymer stabilizers with extended hydrophilic chains exhibited elevated intrapolymer activity from the loss of hydrogen-bond cushioning in dissolution media with heightened ionic strength, confirmed through one-dimensional (1D) 1H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) experiments. Thus, steric repulsion within the affected nanosuspensions was limited and release rates decreased. Additionally, the strength of interaction between hydrophobic polymer components and the API crystalline surface contributed to suspension dissolution properties, confirmed through solution- and solid-state spectroscopic analyses. This study provides a unique perspective on the dynamic interface between the crystalline drug and aqueous microenvironment during dissolution.

Flow-through cell-based in vitro release method for triamcinolone acetonide poly (lactic-co-glycolic) acid microspheres.

The main objective of the current research was to develop a compendial flow-through cell apparatus based in vitro release testing method for sustained-release triamcinolone acetonide-loaded poly (lactic-co-glycolic) acid (PLGA) microspheres. Media-based and instrument-based parameters, such as surfactant type, concentration, media volume, flow rate, and testing temperature, were investigated. In addition, a detailed exploration was performed to reveal polymer degradation encompassing pore formation, channeling, and triamcinolone acetonide release from microspheres using freeze-fracture scanning electron microscopy. The developed USP apparatus 4 method demonstrated more than 85% drug release from the microspheres in 12 days and showcased reproducibility between different microsphere batches. Large medium volume (15 times saturation solubility) at low surfactant concentration was identified as a critical media-based parameter, with potential application in testing of other sensitive poorly soluble drugs. At 35 °C, drug release via pore channeling to the surface was evident, whereas at 39 °C, drug release slowed due to polymer plasticization. It was demonstrated here for the first time that elevated temperature-accelerated testing does not work for all PLGA-based microsphere products.

Probing in Vitro Release Kinetics of Long-Acting Injectable Nanosuspensions via Flow-NMR Spectroscopy.

Novel treatment routes are emerging for an array of diseases and afflictions. Complex dosage forms, based on active pharmaceutical ingredients (APIs) with previously undesirable physicochemical characteristics, are becoming mainstream and actively pursued in various pipeline initiatives. To fundamentally understand how constituents in these dosage forms interact on a molecular level, analytical methods need to be developed that encompass selectivity and sensitivity requirements previously reserved for a myriad of in vitro techniques. The knowledge of precise chemical interactions between drugs and excipients in a dosage form can streamline formulation development and process screening capabilities through the identification of properties that influence rates and mechanisms of drug release in a cost-effective manner, relative to long-term in vivo studies. Through this work, a noncompendial in vitro release (IVR) method was developed that distinguished the presence of individual components in a complex crystalline nanosuspension environment. Doravirine was formulated as a series of long-acting injectable nanosuspensions with assorted excipients, using low- and high-energy wet media milling methods. IVR behavior of all formulation components were monitored using a robust continuous flow-through (CFT) dissolution setup (USP-4 apparatus) with on-line 1H NMR end-analysis (flow-NMR). Results from this investigation led to a better understanding of formulation parameter influences on nanosuspension stability, surface chemistry, and dissolution behavior. Flow-NMR can be applied to a broad range of dosage forms in which specific molecular interactions from the solution microenvironment require further insight to enhance product development capabilities.

The mechanism of solifenacin release from a pH-responsive ion-complex oral suspension in the fasted upper gastrointestinal lumen.

The main objective of this study was to investigate the mechanism of solifenacin release from a pH-responsive ion-complex oral resinate suspension under conditions simulating the environment in the upper gastrointestinal lumen. A secondary objective was to propose an appropriate in vitro methodology for evaluating the quality of orally administered solifenacin suspensions. The mechanism of solifenacin release from polacrilin potassium resin (Amberlite® IRP88) was investigated using biorelevant media and compendial setups (USP Apparatus 2 and USP Apparatus 4) and using newer, recently validated in vitro methodologies [biorelevant gastrointestinal transfer (BioGIT) system]. We evaluated the impact of particle size and concentration of the resin; thickener concentration (carbomer homopolymer, type B); and the impact of pH, cationic strength, agitation intensity and level of simulation of contents in the upper gastrointestinal lumen. Data suggested that solifenacin release from the resinate was determined by the resin particle size, the medium pH, cationic strength (when the conditions in the upper small intestine are simulated) and the level of simulation of contents in the upper small intestine. The interaction of solifenacin with taurocholic acid/lecithin aggregates was significant, but unlikely to affect the degree of solifenacin absorption, as a BCS Class I compound. Under acidic conditions, solifenacin was dissociated and released from the pH-responsive resin rapidly. Under conditions simulating the contents of the upper small intestine, solifenacin was replaced by cations from the testing media and diffused through the resin matrix. All three in vitro systems with or without a pH gradient are useful in distinguishing solifenacin release characteristics from resinate suspensions with different particle sizes. Because of this drug release mechanism, USP Apparatus 2 with fixed pH media demonstrated equivalent or slightly higher discriminative sensitivity than the other setups and appears to be appropriate for product quality control.