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

Objective: Due to quality of generic formulations depends on available information of reference drug products the aim of this work was to perform an in vitro dissolution study of two doses of propranolol-HCl and ranitidine-HCl reference tablets using USP basket or paddle apparatus and flow-through cell method. Methods: Two doses of propranolol-HCl (10-mg and 80-mg) and ranitidine-HCl (150-mg and 300-mg) of Mexican reference products were used. Dissolution profiles of propranolol-HCl were obtained with USP basket apparatus at 100 rpm and 1000 ml of 1% hydrochloric acid. Profiles of ranitidine-HCl were determined with USP paddle apparatus at 50 rpm and 900 ml of distilled water. All formulations were also studied with the flow-through cell method using laminar flow at 16 ml/min. Dissolution profiles were compared by model-independent (f2 similarity factor, mean dissolution time and dissolution efficiency) and model-dependent methods (dissolution data adjusted to some mathematical equations). Time data, derived from these adjustments, as t50%, t63.25%, and t85% were used to compare dissolution profiles. Results: With all approaches used and being high solubility drugs significant differences were found between low and high doses and between USP dissolution apparatuses (*P<0.05). Conclusion: In vitro dissolution performance of two doses of propranolol-HCl and ranitidine-HCl was not expected. Considering the same USP dissolution apparatus, the reference tablets did not allow the simultaneous release of the used doses. The results could be of interest for pharmaceutical laboratories or health authorities that classify some drug products as a reference to be used in dissolution and bioequivalence studies.

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Development and Validation of a Discriminating In Vitro Dissolution Method for Oral Formulations Containing Satranidazole

International Journal of Spectroscopy ◽

10.1155/2014/624635 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Harshal Ashok Pawar ◽

Pooja Rasiklal Joshi

Keyword(s):

Water Solubility ◽

Spectroscopic Method ◽

In Vitro Dissolution ◽

Dissolution Behavior ◽

Solution Stability ◽

Dissolution Medium ◽

Drug Release Profile ◽

Drug Products ◽

Oral Formulations

The development of a meaningful dissolution procedure for drug products with limited water solubility has been a challenge to the pharmaceutical industry. Satranidazole (BCS Class II drug) is a new nitroimidazole derivative with potent antiamoebic action. There is no official dissolution medium available in the literature. In the present study, parameters such as saturation solubility in different pH medium, dissolution behavior of formulations, influence of sink conditions, stability, and discriminatory effect of dissolution testing were studied for the selection of a proper dissolution medium. Results of solubility data revealed that solubility of Satranidazole decreases with an increase in pH. Satranidazole showed better sink condition in 0.1 N HCl as compared to other media. The drug and marketed formulations were stable in the dissolution media used. An agitation speed of 75 rpm showed a more discriminating drug release profile than 50 rpm. Using optimized dissolution parameters (paddle at 75 rpm, 900 mL 0.1 N HCl) greater than 80% of the label amount is released over 60 minutes. UV-spectroscopic method used was validated for the specificity, linearity, precision, robustness, and solution stability. The method was successfully applied to granular formulations and also to marketed tablets containing 300 mg Satranidazole.

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Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

Pharmaceutics ◽

10.3390/pharmaceutics13081109 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1109

Author(s):

Elham Amini ◽

Abhinav Kurumaddali ◽

Sharvari Bhagwat ◽

Simon M. Berger ◽

Günther Hochhaus

Keyword(s):

In Silico ◽

Mass Effect ◽

Dissolution Behavior ◽

Experimental Conditions ◽

Drug Products ◽

Starting Point ◽

Orally Inhaled Drug Products ◽

Model Drug ◽

The Impact

The aim of this study was to further evaluate and optimize the Transwell® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method’s development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called “mass effect”. The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions.

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A Simple Approach for Comparing the In Vitro Dissolution Profiles of Highly Variable Drug Products: a Proposal

The AAPS Journal ◽

10.1208/s12248-018-0238-1 ◽

2018 ◽

Vol 20 (4) ◽

Cited By ~ 3

Author(s):

Marilyn N. Martinez ◽

Xiongce Zhao

Keyword(s):

Simple Approach ◽

In Vitro Dissolution ◽

Drug Products

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Developing Clinically Relevant Dissolution Specifications for Oral Drug Products—Industrial and Regulatory Perspectives

Pharmaceutics ◽

10.3390/pharmaceutics12010019 ◽

2019 ◽

Vol 12 (1) ◽

pp. 19 ◽

Cited By ~ 1

Author(s):

Mark McAllister ◽

Talia Flanagan ◽

Karin Boon ◽

Xavier Pepin ◽

Christophe Tistaert ◽

...

Keyword(s):

In Vitro Dissolution ◽

Oral Drug ◽

Regulatory Agencies ◽

Pharmaceutical Sciences ◽

Drug Products ◽

Future Developments ◽

In Silico Modeling ◽

Regulatory Sciences ◽

Key Questions

A meeting that was organized by the Academy of Pharmaceutical Sciences Biopharmaceutics and Regulatory Sciences focus groups focused on the challenges of Developing Clinically Relevant Dissolution Specifications (CRDS) for Oral Drug Products. Industrial Scientists that were involved in product development shared their experiences with in vitro dissolution and in silico modeling approaches to establish clinically relevant dissolution specifications. The regulators shared their perspectives on the acceptability of these different strategies for the development of acceptable specifications. The meeting also reviewed several collaborative initiatives that were relevant to regulatory biopharmaceutics. Following the scientific presentations, a roundtable session provided an opportunity for delegates to discuss the information that was shared during the presentations, debate key questions, and propose strategies to make progress in this critical area of regulatory biopharmaceutics. It was evident from the presentations and subsequent discussions that progress continues to be made with approaches to establish robust CRDS. Further dialogue between industry and regulatory agencies greatly assisted future developments and key areas for focused discussions on CRDS were identified.

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Quality assessment of nine brands of metformin hydrochloride tablets marketed in Abuja, Nigeria

Journal of Pharmacy & Bioresources ◽

10.4314/jpb.v18i3.6 ◽

2021 ◽

Vol 18 (3) ◽

pp. 216-222

Author(s):

Olubukola A. Odeniran1, ◽

Olubunmi J. Olayemi ◽

Isa H. Galadima, ◽

Rukaiyatu A. Kirim ◽

Christianah Y. Isimi ◽

...

Keyword(s):

Active Ingredient ◽

Type Ii Diabetes ◽

Type Ii Diabetes Mellitus ◽

In Vitro Dissolution ◽

Metformin Hydrochloride ◽

Disintegration Time ◽

Drug Products ◽

First Choice

Metformin is a drug of first choice in management of type II diabetes mellitus and the Nigerian market is flooded with many brands of metformin tablets. The aim of this study is to assess the pharmaceutical quality of nine brands of metformin tablets circulating in pharmacy outlets in Abuja. The brands were assessed for uniformity in weight, hardness, friability, disintegration time and in vitro dissolution using official methods. The content of active ingredient was also determined spectrophotometrically. All the brands had weights within the official limits, hardness was found to differ across the brands with values ranging between 1.20 and 11.50 kgF. Friability values were between 0.00 and 2.25%, disintegration time was between 2.06 and 10.36 min and within official specifications for film-coated tablets. Drug release within 60 min was between 93 and 103%, however, one of the brands fell outside the lower limit of the official specification and therefore, failed the dissolution test. Similarly, all but one of the brands were within the official specification of the percent content of active ingredient. The results highlight the need to routinely carry out market surveillance on drug products so as to safeguard the health of patients.

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Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability

AAPS PharmSciTech ◽

10.1208/s12249-021-02063-1 ◽

2021 ◽

Vol 22 (7) ◽

Cited By ~ 1

Author(s):

Elise Burmeister Getz ◽

Kevin J. Carroll ◽

J. David Christopher ◽

Beth Morgan ◽

Scott Haughie ◽

...

Keyword(s):

Type I Error ◽

Random Effect ◽

Batch Effect ◽

Type I ◽

Drug Products ◽

Orally Inhaled Drug Products ◽

Bioequivalence Testing ◽

Study Participants ◽

Single Batch

AbstractBatch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model (“Superbatch”) or included as a fixed or random effect (“Fixed Batch Effect,” “Random Batch Effect”). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study (“Targeted Batch”). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.

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DISSOLUTION PERFORMANCE OF MELOXICAM FORMULATIONS UNDER HYDRODYNAMICS OF USP PADDLE APPARATUS AND FLOW-THROUGH CELL METHOD

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2019v11i4.33243 ◽

2019 ◽

pp. 182-188

Author(s):

OSE RAUL MEDINA-LOPEZ ◽

JOSE ANGEL OROZCO-JUAREZ ◽

MARCELA HURTADO

Keyword(s):

In Vitro Dissolution ◽

Dissolution Time ◽

Weibull Function ◽

Cell Method ◽

Drug Products ◽

Poorly Soluble ◽

Flow Through ◽

Dissolution Efficiency ◽

Paddle Apparatus

Objective: To study the in vitro dissolution performance of four generic formulations of the poorly soluble drug meloxicam and the reference under hydrodynamic environments generated by flow-through cell method and USP paddle apparatus (pharmacopeial test). Methods: Dissolution method was validated according to ICH guidelines. Dissolution profiles were carried out with an automated flow-through cell apparatus (laminar flow at 16 ml/min with 22.6 mm cells) and USP paddle apparatus at 75 rpm. Phosphate buffer pH 7.5 at 37.0±0.5 °C was used as dissolution medium. Spectrophotometric determination of drug at 362 nm was carried out during 30 min. Dissolution profiles were compared with model-dependent and-independent methods. Results: Practically, all generic formulations showed significant differences with the percentage of drug dissolved at 30 min, mean dissolution time and dissolution efficiency, when USP paddle apparatus was used (*P<0.05), while only two generic formulations were different to reference using flow-through cell method. After adjustment to different mathematical equations, Weibull function was the best model to describe meloxicam dissolution performance and significant differences were found with all drug products when USP paddle apparatus was used, while only one formulation was different with flow-through cell method. Conclusion: The study reveals the need to look for better dissolution schemes for meloxicam tablets since USP paddle apparatus may not reflect properly the in vitro dissolution performance of meloxicam generic formulations and reference.

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International Regulations for Bioequivalence Approval of Locally Acting Orally Inhaled Drug Products

10.22541/au.161019131.19061881/v1 ◽

2021 ◽

Author(s):

Dr. Vinod Gaikwad ◽

Prajakta Patil ◽

Atmaram Pawar ◽

Kakasaheb Mahadik

Keyword(s):

In Vivo Studies ◽

Regulatory Agencies ◽

European Medicines Agency ◽

Drug Products ◽

International Regulations ◽

Orally Inhaled Drug Products ◽

Drug Regulatory Agencies ◽

Health Canada

Bioequivalence (BE) is established between the brand drug and the generic drug to allow the linking of preclinical and clinical testing conducted on the reference listed drug. Regulatory agencies around the globe have come up with the guidance for locally acting orally inhaled drug products (OIDPs) for bioequivalence approaches. The prime intent of the present article is to compare approaches of different international regulatory authorities such as Health Canada, European Medicines Agency and the US Food and Drug Administration that have published guidance related to locally acting OIDPs. Moreover, the Central Drugs Standard Control Organisation, India, has published guidelines for bioavailability and bioequivalence studies. BE recommendations from global regulatory agencies were based on comparison for different parameters, namely inhaler device, formulation, reference product’s selection, in-vitro as well as in-vivo studies (pharmacokinetics, pharmacodynamics, and clinical studies). In the case of in-vivo studies, details about study design, dose choices, inclusion/ exclusion criteria of the subject, study period, endpoint study, and equivalence acceptance criteria were discussed in the present review article.

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