Dissolution Methodology Research Articles

Advancing the Harmonization of Biopredictive Methodologies through the Product Quality Research Institute (PQRI) Consortium: Biopredictive Dissolution of Dipyridamole Tablets.

Biorelevant dissolution and its concept have been widely accepted and further developed to meaningfully predict the bioperformance of oral drug products. Biorelevant methodologies have been applied to design and optimize oral formulations, to facilitate formulation bridging, and to predict the outcome of bioperformance by coupling the results with modeling. Yet, those methodologies have often been independently customized to align with specific aspects of the oral drug products being developed. Therefore, the evolution of biorelevant dissolution methodologies has taken slightly diverse pathways rather than being standardized like compendial quality control (QC) methodologies. This manuscript presents an effort through the Product Quality Research Institute (PQRI, https://pqri.org) consortium entitled: the standardization of "in vivo predictive dissolution methodologies and in silico bioequivalent study working group" to find the key parameters for biorelevant dissolution, to identify the best practices, and to move toward standardization of biorelevant dissolution methodologies. This working group is composed of members from 10 pharmaceutical companies and academic institutes. The consortium project will be accomplished in five phases, whereby the first two phases have already been completed and published. In this paper, the next two phases are addressed by reporting the biorelevant dissolution profiles of dipyridamole, a weak base model drug, then incorporating the dissolution results into physiologically based biopharmaceutics modeling (PBBM) to determine whether they would lead to bioequivalence (BE) or non-BE.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of ‘inhalation biopharmaceutics’ i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using ‘simple’ Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

Optimization of LiF dissolution with Al2(SO4)3 and its application to lithium extraction by fluorination of α-spodumene

Numerous Li extraction methods from minerals and e-waste have been reported in the literature. Among them, direct fluorination processes appear to be a viable alternative due to their high lithium extraction efficiencies (>90%) as LiF. However, a drawback is the low water solubility of LiF, which requires acids for its separation and to obtain other commercial lithium salts. An interesting alternative for dissolving salts with low solubility is through the formation of coordination complexes. In this case, aluminum forms highly stable soluble complexes with the F− anion, such as AlF2+, AlF2+, AlF3, AlF4−, AlF52−, AlF63−.This study proposes an acid-free LiF dissolution methodology using aluminum sulfate as a leaching agent. The LiF dissolution was modeled and optimized using Response Surface Methodology (RSM). The investigated operating parameters for LiF dissolution were the solid/liquid ratio (A), reaction temperature (B), and leaching time (C). Thus, a predictive mathematical model was successfully optimized (R2 = 0.9445). The results indicated that the S/L ratio negatively influences the dissolution of LiF, while temperature and time have a positive effect. The LiF dissolutions of 90 ± 3% were achieved with a leaching time of 31 min, a S/L ratio of 20 g/mL, and a temperature of 45 °C.

Contribution of the Dynamic Intestinal Absorption Model (Diamod) to the Development of a Patient-Centric Drug Formulation.

Compound X is a weak basic drug targeting the early stages of Parkinson's disease, for which a theoretical risk assessment has indicated that elevated gastric pH conditions could potentially result in reduced plasma concentrations. Different in vitro dissolution methodologies varying in level of complexity and a physiologically based pharmacokinetic (PBPK) absorption model demonstrated that the dissolution, solubility, and intestinal absorption of compound X was indeed reduced under elevated gastric pH conditions. These observations were confirmed in a crossover pharmacokinetic study in Beagle dogs. As a result, the development of a formulation resulting in robust performance that is not sensitive to the exposed gastric pH levels is of crucial importance. The dynamic intestinal absorption MODel (Diamod), an advanced in vitro gastrointestinal transfer tool that allows to study the gastrointestinal dissolution and interconnected permeation of drugs, was selected as an in vitro tool for the formulation optimization activities given its promising predictive capacity and its capability to generate insights into the mechanisms driving formulation performance. Different pH-modifiers were screened for their potential to mitigate the pH-effect by decreasing the microenvironmental pH at the dissolution surface. Finally, an optimized formulation containing a clinically relevant dose of the drug and a functional amount of the selected pH-modifier was evaluated for its performance in the Diamod. This monolayer tablet formulation resulted in rapid gastric dissolution and supersaturation, inducing adequate intestinal supersaturation and permeation of compound X, irrespective of the gastric acidity level in the stomach. In conclusion, this study describes the holistic biopharmaceutics approach driving the development of a patient-centric formulation of compound X.

Flurbiprofen cataplasms: Development and validation of in-vitro dissolution methods and evaluation of multimedia dissolution profiles

The investigation of the systemic release performance of dosage forms using in vitro tools is a crucial objective in the realm of pharmaceutical development. The dissolution methodology is an effective tool for monitoring batch-to-batch variabilities in quality control and gaining insight into the release mechanisms of pharmaceutical drugs. The majority of the dissolution techniques that have been approved are primarily intended for solid oral dosage forms. Nevertheless, these techniques have also been applied to various other dosage forms, including transdermal drug delivery systems. The administration of medication through cataplasm, a transdermal application, poses challenges in understanding the characteristics of drug release. Flurbiprofen is classified as a class II drug according to the Biopharmaceutics Classification System and is commonly administered in the form of a cataplasm for its analgesic properties. A dissolution method was developed to assess the in vitro release profile of the flurbiprofen transdermal delivery system. This method utilized a United States Pharmacopeia dissolution apparatus V, with a disc assembled over the paddle. Additionally, a method for quantification was developed using liquid chromatography. The discriminatory aspect of the developed method has faced criticism due to substantial alterations in excipient composition. Furthermore, we have developed clearly defined multimedia release profiles within the physiological pH range. The validation of the dissolution and chromatography systems was conducted.

Integration of Biorelevant Pediatric Dissolution Methodology into PBPK Modeling to Predict In Vivo Performance and Bioequivalence of Generic Drugs in Pediatric Populations: a Carbamazepine Case Study

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive dissolution profile. Dissolution profiles of CBZ IR tablets (100 mg) were generated in 50–900 mL biorelevant adult fasted state simulated gastric and intestinal fluid (Ad-FaSSGF and Ad-FaSSIF), also in three alternative compositions of biorelevant pediatric FaSSGF and FaSSIF medias at 200 mL. This study found that CBZ dissolution was poorly sensitive to changes in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 μM (Ad-FaSSIF vs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolution data for CBZ 100 mg (reference and generic test) IR product. The CBZ PBPK models showed bioequivalence of the product. This study demonstrates that the integration of biorelevant dissolution data can predict the PK profile of a poorly soluble drug in both populations. Further work using more pediatric drug products is needed to verify biorelevant dissolution data to predict the in vivo performance in pediatrics.Graphical

Harmonizing Biopredictive Methodologies Through the Product Quality Research Institute (PQRI) Part I: Biopredictive Dissolution of Ibuprofen and Dipyridamole Tablets

Assessing in vivo performance to inform formulation selection and development decisions is an important aspect of drug development. Biopredictive dissolution methodologies for oral dosage forms have been developed to understand in vivo performance, assist in formulation development/optimization, and forecast the outcome of bioequivalence studies by combining them with simulation tools to predict plasma profiles in humans. However, unlike compendial dissolution methodologies, the various biopredictive methodologies have not yet been harmonized or standardized. This manuscript presents the initial phases of an effort to develop best practices and move toward standardization of the biopredictive methodologies through the Product Quality Research Institute (PQRI, https://pqri.org) entitled “The standardization of in vitro predictive dissolution methodologies and in silico bioequivalence study Working Group.” This Working Group (WG) is comprised of participants from 10 pharmaceutical companies and academic institutes. The project will be accomplished in a total of five phases including assessing the performance of dissolution protocols designed by the individual WG members, and then building “best practice” protocols based on the initial dissolution profiles. After refining the “best practice” protocols to produce equivalent dissolution profiles, those will be combined with physiologically based biopharmaceutics models (PBBM) to predict plasma profiles. In this manuscript, the first two of the five phases are reported, namely generating biopredictive dissolution profiles for ibuprofen and dipyridamole and using those dissolution profiles with PBBM to match the clinical plasma profiles. Key experimental parameters are identified, and this knowledge will be applied to build the “best practice” protocol in the next phase.Graphical

Development of In Vitro Dissolution Testing Methods to Simulate Fed Conditions for Immediate Release Solid Oral Dosage Forms.

In vitro dissolution testing is widely used to mimic and predict in vivo performance of oral drug products in the gastrointestinal (GI) tract. This literature review assesses the current in vitro dissolution methodologies being employed to simulate and predict in vivo drug dissolution under fasted and fed conditions, with emphasis on immediate release (IR) solid oral dosage forms. Notable human GI physiological conditions under fasted and fed states have been reviewed and summarized. Literature results showed that dissolution media, mechanical forces, and transit times are key dissolution test parameters for simulating specific postprandial conditions. A number of biorelevant systems, including the fed stomach model (FSM), GastroDuo device, dynamic gastric model (DGM), simulated gastrointestinal tract models (TIM), and the human gastric simulator (HGS), have been developed to mimic the postprandial state of the stomach. While these models have assisted in expanding physiological relevance of in vitro dissolution tests, in general, these models lack the ability to fully replicate physiological conditions/processes. Furthermore, the translatability of in vitro data to an in vivo system remains challenging. Additionally, physiologically based pharmacokinetic (PBPK) modeling has been employed to evaluate the effect of food on drug bioavailability and bioequivalence. Here, we assess the current status of in vitro dissolution methodologies and absorption PBPK modeling approaches to identify knowledge gaps and facilitate further development of in vitro dissolution methods that factor in fasted and fed states. Prediction of in vivo drug performance under fasted and fed conditions via in vitro dissolution testing and modeling may potentially help efforts in harmonizing global regulatory recommendations regarding in vivo fasted and fed bioequivalence studies for solid oral IR 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.

Methodology for dissolution of sediment and calcareous deposits for paleontological specimen collection and identification

The Lance Creek Formation (Late Cretaceous) is significant in the study of late dinosaurs and is a diverse formation containing both terrestrial and aquatic macrofossils. To study this important ecosystem, all of the fossils present must be uncovered and examined from Lance Creek sedimentary rocks, which exhibit variable degrees of lithification. In order to liberate the fossils, a dissolution methodology was designed to determine which solution was most effective at uncovering specimens and dissolving/disaggregating sediment. Different solutions were tested including water, a 50% Calgon© solution, and a 5% acetic acid solution. The control was a sedimentary rock sample not subjected to any solutions prior to rinsing and sieving. A small-scale dissolution (10 g of loose sediment) was performed using each solution and examined for fossils. Acetic acid was deemed the most effective solution for the dissolution of dense sandstones, and indurated sediment from the Lance Creek Formation. Large-scale disaggregation (800 g of consolidated sedimentary rock) yielded abundant terrestrial, fluvial, and marine macrofossils. Macrofossil disaggregation using these methods has the potential to yield a more diverse assemblage of contemporaneous fossils than macrofossils alone, and can therefore provide substantial insight into ecological reconstructions.•A small-scale study was done to determine which solution was the most efficient at dissolution of sediment. Acetic acid was deemed the most effective.•A large-scale experiment was done on dense sandstones using 5% acetic acid and a shaking incubator.•A large-scale experiment of indurated sediment was performed using 5% acetic acid.

Development and validation of a dissolution test for empagliflozin in film-coated tablets

The present study proposes a validated dissolution method for empagliflozin (EMPA) in film coated tablets. A gradual in vitro dissolution profile for this formulation was obtained using 900 mL of hydrochloric acid 0.01 M at 37 °C ± 0.5 °C as dissolution medium and USP apparatus 2 (paddle) at 50 rpm. The dissolved percentage of EMPA was quantified by ultraviolet spectrophotometric method to obtain cost technique and produce little residual solvents. Validation parameter for dissolution methodology such as the specificity, linearity, accuracy and precision were evaluated according to the international guidelines, giving results within the acceptable range. The method is linear in the range of 1 - 40 µg/mL, precise, with RSD value less than 2.62%, accurate (mean recovery 106.97%) and robust. Therefore, since no official method has been described, the proposed dissolution conditions represent a relevant contribution to evaluate the dissolution profile of coated tablet containing 25 mg of EMPA.

Dry powder inhaler formulation comparison: Study of the role of particle deposition pattern and dissolution

The composition, morphology and dissolution profile of particles and micro-sized agglomerates delivered upon inhalation may have a significant impact on the product clinical effect. However, although several efforts are ongoing, a methodology that considers deposition structures and dissolution performance evaluation in a biorelevant set-up is not yet standardized. The goal of this work is to apply a collection and dissolution methodology able to discriminate dry powder inhaler (DPI) formulations in terms of deposition structures and dissolution profile in vitro. Hence, Fluticasone Propionate (FP) engineered particles and formulated products (used as a case study) were collected employing a breath simulator and characterized regarding (i) aerodynamic particle size distribution; (ii) deposited microstructures; and (iii) dissolution/absorption profiles using the DissolvIt® bio-relevant dissolution equipment. The results indicated that the particle engineering technology had an impact on the generated and deposited microstructures, here associated to the differences on surface properties of jet milled and wet polished particles quantified by the specific surface area. Differences on surface properties modulate particle interactions, resulting in agglomerates of drug substance and excipient upon actuation with significant different morphologies, observed by microscope, as well as quantified by Marple cascade impactor. These observations allow for a further understanding of the DPI aerosolization and deposition mechanisms. The dissolution and absorption assessment indicates that the presence of lactose may accelerate the drug substance dissolution kinetics, and the FP dissolution can be significantly enhanced when formulated as a spray-dried dispersion particle. Ultimately, the results suggest dissolution testing can be an essential tool to both optimize an innovator DPI and de-risk generics development.

Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution.

Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two successful strategies, yet there are opportunities for further development. For ASDs, drug-polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)-poly(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.

An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products.

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

A simple hplc method for In-vitro Dissolution study of brivaracetam in pharmaceutical dosage form

Brivaracetam is a racetam derivative of levetiracetam having prominent activity against epilepsy. Objective of the proposed work was to develop and validate a new In-Vitro dissolution methodology for quantitation of % Brivaracetam release fromtablets using HPLC analysis. No official HPLC method has been published yet for the dissolution study of Brivaracetam. All the dissolution parameters have been optimized for quantitation purpose. Initially, 900ml of 0.05M Potassium dihydrogen phosphate buffer (pH 6.4) has taken as a dissolution medium, using a paddle apparatus operated at 75rpm for 45 minutes. Chromatographic analysis has been carried out on C18 column (Inertsil ODS 3V HPLC Column having dimensions of 150 mm × 4.6mm, 5μm), isocratic analysishas been conductedwith mobile phase containing a mixture of 0.1%v/v trifluoroacetic acid in water and acetonitrile (60:40 v/v) at a flow rate of 1.0mL/min with the elution monitored at wavelength of 210 nm and column oven temperature of 30°C. The method was further validated to meet the requirements of regulator. The dissolution method of analysis developed was adequate for its purpose and could be employed for the routine quality control of Brivaracetam tablets.

The Introduction of a New Flexible In Vivo Predictive Dissolution Apparatus, GIS-Alpha (GIS-α), to Study Dissolution Profiles of BCS Class IIb Drugs, Dipyridamole and Ketoconazole

The physiological pH changes and peristalsis activities in gastrointestinal (GI) tract have big impact on the dissolution of oral drug products, when those oral drug products include APIs with pH-dependent solubility. It is well documented that predicting the bioperformance of those oral drug products can be challenging using compendial methods. To overcome this limitation, in vivo predictive dissolution apparatuses, such as the transfer model, have been developed to predict bioperformance of oral formulation candidates and drug products. In this manuscript we utilize a new transfer-model dissolution apparatus, the gastrointestinal simulator-α (GIS-α), to characterize its behavior in terms of transfer kinetics and pH, assess its reproducibility and adaptability to mimic different transfer conditions, as well as study dissolution of ketoconazole and dipyridamole as model BCS class IIb compounds. Availability of commercially available dissolution transfer systems with similar configuration to compendial dissolution apparatus, may be helpful to simplify and standardize in vivo predictive dissolution methodologies for BCS class IIb compounds in the future.

Ultrathin, Large-Area Membrane Diffusion Cell for pH-Dependent Simultaneous Dissolution and Absorption Studies.

Preclinical evaluation of modern oral dosage forms requires more advanced in vitro devices as the trend of selecting low solubility, high permeability compounds for commercial development continues. Current dissolution methodologies may not always be suitable for such compounds due to excessive fluid volume, high fluid shear rates, heterogeneity of shear rates, suboptimal fluid flow, and, ultimately, the lack of absorption ability (Gray The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance; Pharmaceutical Research, 2009; Vol. 26; pp 1289-1302). Herein, a new dissolution apparatus is introduced in combination with an ultrathin, semipermeable polymer membrane that mimics human passive absorption for lipophilic compounds. The ultrathin large-area polydimethylsiloxane (PDMS) membrane (UTLAM) absorption system is designed to mimic the dissolution and passive transcellular diffusion process representing the oral absorption pathway. A simple spin-casting method was developed to fabricate the ultrathin highly uniform membranes. To minimize membrane resistance to diffusion and maximize transport across the polymer membrane, 10-40 μm PDMS membranes were successfully prepared. A new diffusion cell was designed and tested to support the UTLAM and incorporates a hydrofoil impeller for more desirable hydrodynamics and mixing, using ibuprofen as a model weak acidic drug. UTLAM permeability was sufficiently high that the aqueous boundary layer contributed to the overall permeability of the system. This diffusion cell system demonstrated that, when the aqueous diffusion layer contributes to the overall resistance to transport, the pH at which absorption is 50% of maximum (pH50%) shifts from the pKa to higher values, demonstrating why weak acid drugs can exhibit high absorption at pH's significantly greater than their pKa. High rates of transport across the UTLAM are possible for drugs with high partition coefficients (i.e., BCS II compounds even under mostly ionized conditions), and PDMS UTLAMs may be tailored to simulate human intestinal passive absorption rates.

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.

Development and Evaluation of Bioresponsive Tablets of a Selective COX-2 Inhibitor for Colonic Delivery

Background: We report the effectiveness of a targeted delivery system containing Meloxicam using polysaccharides for the treatment of colorectal cancer. We also propose a novel biorelevant dissolution method to overcome drawbacks of existing dissolution methodologies of polysaccharidebased systems. The proposed method includes a mixture of probiotics cultured under anaerobic conditions in the presence of prebiotic in the in vitro dissolution study to surrogate colonic conditions. Polysaccharide- based system can be simple, safe and effective drug delivery system to target drugs to colon. Methods: Press-coated tablets of Meloxicam were prepared by direct compression using various polysaccharides, such as xanthan gum, guar gum and pectin as coating polysaccharides. Developed tablets were evaluated for physical parameters, lag phase and in vitro drug release. Developed probioticsbased dissolution method was validated and explored for versatility using other polysaccharides. Results: Press-coated tablets of Meloxicam were successfully developed exhibiting targeted delivery to the colon using guar gum as coat and releasing more than 80% of drug in simulated colonic fluid. The developed probiotics based dissolution method may prove to be useful as a bio-relevant and discriminatory method. Conclusion: Developed Meloxicam tablets press-coated with guar gum can be taken orally for treatment or as an adjuvant therapy in colon cancer. Polymers used in this formulation are abundant, nontoxic, biodegradable and inexpensive which make this a a very promising approach for the treatment of different colonic diseases. The proposed biorelevant, animal sparing, probiotics based dissolution medium was found to be versatile to study drug release from other polysaccharide based formulations for colonic delivery.

Method development and validation of dissolution testing for nicotine release from smokeless tobacco products using flow-through cell apparatus and UPLC-PDA

Developing dissolution testing methods to measure the nicotine release profiles from smokeless tobacco products is valuable for product assessment and product-to-product comparisons.In this work, we developed a robust dissolution method to study the in vitro release of nicotine from smokeless tobacco products using the U.S. Pharmacopeia flow-through cell dissolution apparatus 4 (USP-4). We further developed and validated a sensitive Ultra Performance Liquid Chromatography coupled to Photodiode Array detector (UPLC-PDA) method for the accurate quantitation of the released nicotine into artificial saliva, which is our selected dissolution medium. We have successfully shown the applicability of the validated method by investigating the release profiles of nicotine from various commercial and CORESTA reference smokeless tobacco products [CRP 1.1 (Swedish-style snus pouch), CRP 2.1 (American-style loose moist snuff), CRP 4 (loose-leaf chewing tobacco) and CRP 4.1 (chopped loose-leaf chewing tobacco)]. Nicotine release profiles were analyzed by calculating the difference factor (f1) and similarity factor (f2) by adopting a methodology referenced in the Guidance for Industry from FDA’s Center for Drug Evaluation and Research (CDER) and by fitting the release profile curves using a first order kinetic model. Nicotine release was found to be dependent on the form and cut of the smokeless tobacco products, with a slower release observed for snus and loose-leaf, compared to chopped and loose moist snuff smokeless tobacco. This dissolution methodology can be extended to measure and compare release of other constituents from smokeless tobacco products and has the potential for method standardization.