Wet Granulation Research Articles

Technology Transfer and Process Validation of Metformin Hydrochloride Immediate Release Tablet

Metformin Hydrochloride, inhibits the mitochondrial respiratory chain in the liver, leading to activation of AMPK, enhancing insulin sensitivity (via effects on fat metabolism) and lowering cAMP, thus reducing the expression of gluconeogenic enzymes. Metformin improves blood sugar levels by lowering the amount of glucose (sugar) that we absorb from our diet. It also helps stop the production of new glucose and improves insulin sensitivity. Metformin Hydrochloride is videly used in the form of sustained release formulation of Tablets. The study aimed to formulate and validate novel process for the Metformin Hydrochloride in immediate release pharmaceutical solid dosage forms. The wet granulation method used for formulation of Metformin Hydrochloride Immediate Release Tablets. Metformin Hydrochloride 500 mg, 850 mg, 1000 mg film coated tablets was prepared using FBE granulation technology on lab scale size. This study was carried out through a systematic plan; critical parameters were optimized to engender a stable & robust manufacturing process. The result of all three batches & its critical steps clearly shows consistency & reproducibility of parameters and all results. Hence the manufacturing method of Metformin Hydrochloride 500 mg, 850 mg, 1000 mg Film Coated tablets are validated at above parameters & equipments. Three validation batches of commercial scale batch size were taken successfully and monitored the in-process critical parameters for commercial batches. Metformin Hydrochloride tablets were manufactured within specified Limits for meeting all quality attributes and loaded for stability study. The overall successful three consecutive validation batches of Metformin Hydrochloride film coated tablets (500, 850 & 1000 mg) verifies the international technology transfer success.

Material Transport Characteristics in Planetary Roller Melt Granulation.

Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as these have an enhanced potential to reduce product quality fluctuations. Concerning both aspects, the use of a planetary roller granulator is consequential. The process control with these machines benefits from the enhanced ratio of heated surface to processed volume, compared to the usually-applied twin-screw systems. This is related to the unique concept of planetary spindles flowing around a central spindle in a roller cylinder. Herein, the movement pattern defines the transport characteristics, which determine the energy input and overall processing conditions. The aim of this study is to investigate the residence time distribution in planetary roller melt granulation (PRMG) as an indicator for the material transport. By altering feed rate and rotation speed, the fill level in the granulator is adjusted, which directly affects the average transport velocity and mixing volume. The two-compartment model was utilized to reflect these coherences, as the model parameters symbolize the sub-processes of axial material transport and mixing.

Evaluation of Processing Methods for Formulated Tablets of <i>Loranthus micranthus</i>

Background: Loranthus micranthus is one of the many plants that has documented evidence of safety and efficacy in the management of many ailments and widespread use in almost every part of Nigeria. It is desirable to formulate it into a suitable dosage form for use by the populace.
 Objectives: The research was aimed at formulating the aqueous leaf extract of L. micranthus into a tablet dosage form by wet granulation and direct compression methods.
 Methods: For wet granulation method, maize starch, gelatin, polyvinyl pyrrolidone and acacia were used as binders for the formulations each was used at 2, 3, 4 and 5 % w/w concentration in the tablet. The direct compression method involved the preparation of an extract containing material (ECM). Microcrystalline cellulose, pregelatnised starch, starlac and spray dried lactose were used as filler binders for the direct compression. All the formulated tablets were assessed by comparing the crushing strength-friability ratio (CSFR) and the disintegration time (DT) to select an optimum formulation that meets both mechanical and release properties.
 Results: Using wet granulation method, maize starch and gelatin (at 3 %w/w) binder concentration as well as gelatin at 2 %w/w binder concentration produced the optimal formulations. The tablets formulated by direct compression all disintegrated within 10 min and below with microcrystalline cellulose (MCC) tablets disintegrating at 7 min. In dissolution studies, all the optimized formulations released more than 70 % of the extract within 40 min with MCC releasing up to 98 % in 30 min.
 Conclusion: Direct compression of the extract containing material produced improved tablet formulations than the wet granulation method.

Formulation Development and Characterization of Floating Drug Delivery System of Rosiglitazone Maleate

In the current study, wet granulation with various concentrations and combinations of excipients like magnesium stearate as a lubricant, talc as glident, DCP as diluent, and PVP K 30 as a binder successfully produced floating tablets of rosiglitazone maleate. These excipients included HPMC K15M, xanthan gum, sodium bicarbonate, and tartaric acid as gas-generating agents. We investigated every pre-compressional parameter, including angle of repose, bulk density, and Carr's index. Drug content, hardness, friability, weight fluctuation, in-vitro dissolving experiments, floating qualities, and stability investigations were performed on the compressed tablets. According to in-vitro experiments, the release time increases up to 6, 8, and 10 hours, respectively, as the content of HPMC K15M in formulations F1, F2, and F3 is raised. For formulations F4, F5, and F6, adding xanthan gum raised the release to 7, 9, and 11 hours, respectively. In formulations F7, F8, and F9, the release was found to be increased up to 8, 10, and 12 hours, respectively, with the addition of HPMC K 15 M and Xanthan gum. F9 was discovered to be the finest formulation since it could maintain release for up to 12 hours. All formulations displayed "n" value for Peppa's plot in the range of 0.45 to 0.89, demonstrating anomalous transport (non-Fickian diffusion) as the method of drug release. The improved formulation (F9) was demonstrated to be stable and intact without any contact over the course of 90 days.

Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation.

Risk control for nitrosamine impurities in drug products is currently a major challenge in the industry. Nitrosamines can form during drug product manufacturing and storage through the reaction of nitrites with amine-containing APIs or impurities. The level of nitrites in excipients and the rate of reaction often control the build-up of nitrosamine. Although the variability in nitrite levels across excipient types and suppliers is well recognized, the impact of excipient selection on the level of nitrosamine formed has not been systematically studied. This gap of knowledge is addressed in the current work. We present theoretical case studies of formulations where microcrystalline cellulose (MCC), or lactose supplier, or superdisintegrant type are changed in pursuit of lower levels of nitrite. The impact of the average, maximum, and minimum levels of nitrites in each excipient on nitrosamine formation in the dosage form is calculated. The input data for this calculation are the formulation composition, nitrosamine molecular weight (MW), percentage of conversion, and nitrite levels per excipient. The percentage of conversion (based on the formulation and manufacturing variables) and nitrite levels were taken from the recent literature. We show that changing the supplier of a single excipient, or of the three most critical excipients, can reduce nitrosamine formation by up to -59% and -89%, respectively. We also show that high-risk formulations, e.g., high MW nitrosamines, high dosage weights, and high percentages of conversion (e.g., wet granulation), can often be de-risked below regulatory acceptable daily intake via careful excipient selection. Finally, we provide an open-access tool that enables users to calculate the theoretical formation of nitrosamines in their specific formulations. This calculation template can be used for (i) the preliminary screening of the risk of nitrosamine formation in drug products and (ii) the preliminary assessment of the impact of excipient selection for risk mitigation.

Application of I-Optimal Design for Modeling and Optimizing the Operational Parameters of Ibuprofen Granules in Continuous Twin-Screw Wet Granulation.

The continuous twin-screw wet granulation (TSWG) process was investigated and optimized with prediction-oriented I-optimal designs. The I-optimal designs can not only obtain a precise estimation of the parameters that describe the effect of five input process parameters, including the screw speed, liquid-to-solid (L/S) ratio, TSWG feed rate, and numbers of the 30° and 60° mixing elements, on the granule quality in a TSWG process, but it can also provide a prediction of the response to determine the optimum operating conditions. Based on the constraints of the desired granule properties, a design space for the TSWG was determined, and the ranges of the operating parameters were defined. An acceptable degree of prediction was confirmed through validation experiments, demonstrating the reliability and effectiveness of using the I-optimal design method to study the TSWG process. The I-optimal design method can accelerate the screening and optimization of the TSWG process.

Formulation Development of Tolperisone Hydrochloride Film Coated Tablet

Among all the different routes of administration, oral route of administration continues to be the most preferred route due to various advantages including ease of ingestion, avoidance of pain, versatility and most importantly patient compliance. Likewise, among all dosage forms tablet is the most popular dosage form existing today because of its convenience of self-administration, compactness and easy manufacturing. Sometimes immediate onset of action is considered obligatory immediate release tablets are the final option. Recently immediate release tablets have started gaining popularity and acceptance as a drug delivery system, mainly because they are easy to administer and lead to better patient compliance. In the present work, we engage in discussion about formulation, development, and evaluation of immediate release tablets. An immediate release dosage form allows a manufacturer to extend market exclusivity. They are also a tool for expanding markets, extending product life cycles and generating opportunities. pharmaceutical products designed for oral delivery and currently available on the prescription and over-the-counter markets are mostly the immediate release type, which are designed for immediate release of drug for rapid absorption. Tolperisone Hydrochloride Film Coated Tablets 50 mg was prepared using various excipients listed as in formula. The tablets were prepared by wet granulation method using concave plane punch on multi-station compression machine. The formulations were evaluated for their physical characteristics like thickness, hardness and friability, weight variation, content uniformity study was carried out. Evaluated for chemical analysis like Assay, disintegration and dissolution. In-vitro comparative dissolution study was performed with the help of U.S.P dissolution test apparatus-II with 900 ml of 0.1 N HCL, Acetate buffer pH 4.5 & 0.1 M HCL Acid at the 75 rpm for 45min.

FORMULATION AND EVALUATION OF CEFUROXIME AXETIL GRANULES FOR ORAL SUSPENSION

Objectives: The aim of this study is formulation and evaluation of cefuroxime axetil (CA) granules for oral suspension and to compare its in vitro bioavailability with Innovator Product. Methods: The granules of CA were prepared by wet granulation method. Six formulations of varying composition of ingredients were prepared. Preformulation studies were performed. The suspension was evaluated for its flow property, in vitro dissolution study, and assay. Results: Preformulation parameters show that the flow property of powder is poor. The suspension was successfully prepared by wet granulation method. The flow property of granules varied form fair to excellent in different formulations. The f2value ranges from 25 to 77. Conclusion: With a better release characteristic and excellent flow property, the formulation F6 is considered as the final formulation with an f2 value of 77 and assay of 99.7%.

Pharmaceutical Application of Process Understanding and Optimization Techniques: A Review on the Continuous Twin-Screw Wet Granulation.

Twin-screw wet granulation (TSWG) is a method of continuous pharmaceutical manufacturing and a potential alternative method to batch granulation processes. It has attracted more and more interest nowadays due to its high efficiency, robustness, and applications. To improve both the product quality and process efficiency, the process understanding is critical. This article reviews the recent work in process understanding and optimization for TSWG. Various aspects of the progress in TSWG like process model construction, process monitoring method development, and the strategy of process control for TSWG have been thoroughly analyzed and discussed. The process modeling technique including the empirical model, the mechanistic model, and the hybrid model in the TSWG process are presented to increase the knowledge of the granulation process, and the influence of process parameters involved in granulation process on granule properties by experimental study are highlighted. The study analyzed several process monitoring tools and the associated technologies used to monitor granule attributes. In addition, control strategies based on process analytical technology (PAT) are presented as a reference to enhance product quality and ensure the applicability and capability of continuous manufacturing (CM) processes. Furthermore, this article aims to review the current research progress in an effort to make recommendations for further research in process understanding and development of TSWG.

Viscoelastic response of confined powder under large strain oscillations, characterized by its noise temperature

We report a study on granular matter with and without small additions of silicon oil, under low-frequency and large amplitude oscillatory shear strain under constant normal pressure, by running experiments with a rotational rheometer with a cup-and-plate geometry. We analysed the expansion with the Chebyshev polynomials of the orthogonal decomposition of stress–strain Lissajous–Bowditch loops. We found the onset of the strain amplitude for the yielding regime indicated a regime change from filament-like structures of grains to grain rearrangements for the dry granulate and from oscillations to the breaking and regeneration of liquid bridges for wet granulates. We have shown that this viscoelastic dynamics can be characterized by a noise temperature following Sollich et al. (Phys Rev Lett https://doi.org/10.1103/PhysRevLett.78.2020, 1997). The analysis of the first harmonics of the Chebyshev expansion showed that the state of disorder of dry and wet granular matter in pre-yielding and yielding regimes involved ensembles of different inherent states; thus, each of them was governed by a different noise temperature. The higher-order harmonics of the Chebyshev expansion revealed a proportionality between the viscous nonlinearity and the variation in the elastic nonlinearity induced by the deformation, which shows the coupling between the elastic deformation and the viscous flow of mesoscopic-scale structures.Graphic abstract

Formulation of Dispersible Ayurvedic Kadha Tablet for the Management of Cold and Cough

The term “Ayurveda” combines the Sanskrit words ayur (life) and veda (science or knowledge). It is one of the traditional medicinal systems, with an established history of many centuries. Indian herbs, which are widely used in the preparation of Ayurvedic medicines in the form of Kadha to control various respiratory disorders such as, cough, cold and flu. In a traditional Kadha (decoction) preparation, the entire process is done manually Such as boiling, filtering and mixing of medicinal herbs and the aim of this research work was to skip all such manually process. The oral route of drug administration is most extensively used due to the obvious ease of administration. Dispersible tablets are a vital tool in keeping our children and elderly population healthy. Their ease of use and accurate dosing allow higher patient compliance and more reliable therapeutic effects. Medicinal plants and parts as like Tulsi (Rama-Tulsi) (Ocimum Sanctum Linn, family Lamiaceae), Ginger (Zingiber officinale, family Zingiberaceae), Clove (Syzygium aromaticum, family myrtaceae) and Turmeric (Curcuma longa, family Zingiberaceae) were used as a model drug. Phytochemicals present in these herbs, which have significant potential to heal cold and cough. The phytochemicals present in these herbs possess significant anti-inflammatory property. In order to determine the most effective type and optimal amount of superdisintegrants for dispersible tablets different formulation were evaluated. Wet granulation and direct compression methods were tried to develop dispersible tablet. Due to higher moisture in the granules the wet granulation method was not carried out further in the study and direct compress method was selected. Prepared tablets were tested for Appearance, Weight variation, Thickness, Friability (%), Hardness (kg/cm2 ), Disintegration time and IR spectroscopic analysis and finally for six months of stability studies at room temperature, 30ºC/60% RH and at 45ºC/75% RH. Sodium Starch Glycolate was superior to the other disintegrants and the non-fractionated granulation gave adequate dispersion. The ideal concentration was 1.33 % Sodium Starch Glycolate was used for the dispersible tablets

Formulation and Evaluation of Gastroretentive Floating Tablets of Glipizide

Abstract: The present study outlines a systematic approach for designing and development of Glipizide floating tablets to enhance the bioavailability and therapeutic efficacy of the drug. Floating tablets of Glipizide have shown controlled release thereby proper duration of action at a particular site and are designed to prolong the gastric residence time after oral administration. Different formulations were formulated by wet granulation technique using HPMC K100M (floating agent) and Xanthan gum as polymers along with sodium bicarbonate as gas generating agent. The formulations were evaluated for their physicochemical properties, buoyancy lag time, total floating time, swelling index and in­vitro drug release. It was found that the hardness of the tablets affects the Buoyancy characteristic of the dosage form. All nine formulations possessed good floating properties with total floating time between 8 – 12 hrs.

Production of effervescent tablets of rosela flower (Hibiscus sabdariffa L.) and its effect on the in vivo immune system

Rosella effervescent tablet is an effervescent product in the form of tablet made from roselle petal extract. This study aimed to evaluate the antioxidant content of the resulting effervescent tablets and the effect of effervescent tablets on the in vivo immune system. The technique for making effervescent tablets used the wet granulation method. Immune system analysis used rat test animals. The type of rat is Sprague Dawley. There were three treatment groups, each group consisted of 5 rats. The first group was the standard group, group 2 was the positive control group which was given Stimuno Forte at a dose of 1.35 mg/kg BW, and the treatment group 3 was given roselle effervescent tablets at a dose of 8.1 mg/kg BW by sonde for 28 days. Blood sampling (leukocytes, differential leukocytes, lymphoid organs (spleen and liver), total serum protein, and serum albumin) was performed on day 0 and day 29. The chemical test results of the effervescent tablets showed an IC50 of 10.35 ppm, a vitamin C content of 2.28 mg/tablet, and an anthocyanin content of 22.12 mg/L. The results of the research on rosella effervescent tablets at a dose of 8.1 mg/kg BW provided a protective effect on the immune system of rat with an average parameter of leukocyte count of 7.58×103/µL, total serum protein of 10.25 g/dl, and relative liver weight of 3. 11% and still within the normal range of Sprague Dawley rats.

Formulation and Evaluation of Sustained Release Matrix Tablet Metformin Hydrochloride

Abstract: The present study outlines a systematic approach for designing and development of Metformin Hydrochloride sustained release matrix tablets. Different formulations were formulated by wet granulation technique using Xanthan gum and HPMC K100M as polymers along with other excipients The formulations were evaluated for their physicochemical properties.

DESIGN, FORMULATION, AND IN-VITRO EVALUATION OF IMMEDIATE RELEASE TABLET OF ETORICOXIB USING QUALITY BY DESIGN (QbD) APPROACH

Introduction: The current research aimed to formulate and evaluate the immediate-release tablet of etoricoxib. Etoricoxib belongs to BCS class II drugs; hence the solubility was enhanced using different techniques, thus achieving the dissolution of the drug. The formulation with maximum solubility enhancement was selected as the final formulation for the preparation of immediate-release tablets. Material and Methods: These tablets were prepared using the wet granulation technique. Sodium starch glycolate was used as a super disintegrant, microcrystalline cellulose was used as a binder, and sodium bicarbonate was used as effervescent material for the preparation of an immediate-release tablet. Different trial batches were prepared and the formulations were optimized using design expert software. The optimized formulation was prepared and evaluated for different post-compression parameters. Results and Discussion: The disintegration time was found to be 2 minutes 16 seconds and the percent cumulative drug release was found to be 90.30%. The pharmacokinetic behavior of the drug was studied and first-order kinetics was found to be the best fit model for immediate-release tablets. The accelerated stability study for the immediate-release tablet was carried out at 40℃ ±75% RH and different parameters were evaluated and were found within specified limits. Conclusion: Thus immediate release tablets of etoricoxib were found to be a promising candidate for the treatment of acute pain or arthritis.

Formulation and Pharmaceutical Quality Evaluation of Tablets Containing Extract of Cinnamomum burmannii BARK and Colocasia esculenta (L) Schott Leaves

Cinnamon bark (Cinnamomum burmannii) is used traditionally and has an ingredient containing cinnamic acid compounds. Colocasia esculenta (L) Schott leaves contains of flavonoids, alkaloids, tannins, saponins, steroids, and terpenoids. Both of the plants C. esculenta and C. burmannii plants have the potential as anti-diabetics because they can lower blood glucose levels. This study aims to make combination tablets of C. burmannii bark and C. esculenta leaves extract with various concentrations of PVP K30 binder. This research made four formulas with the concentration of PVP K30, namely F1 (2%), F2 (3%), F3 (4%), and F4 (5%). Tablet preparations were prepared by the wet granulation method. Tablet analysis used flavonoids quercetin and cinnamic acid as markers. The results showed that the tablets were flat, round in shape, light green, had a slightly bitter taste, and had a distinctive aromatic odor. The differences in the concentration of PVP K30 binder 2-5% could affect the hardness, friability, disintegration time, and tablet dissolution (p<0.05). The tablet's hardness was 3.65-5.01 KP; friability was 0.705%, disintegration time was <15 minutes, and dissolution was 84.61% in 40 minutes. The levels of the flavonoid quercetin in the tablets were 4.21% and 8.03% cinnamic acid. A tablet combination of C. burmannii bark and C. esculenta leaves extract with a PVP K30 concentration of 5% (F4) has the best quality.

Data-Knowledge-Driven Modeling and Operational Adjustment for the Pharmaceutical Tablet Manufacturing Process via Wet Granulation.

In the context of Pharma 4.0, pharmaceutical quality control (PQC) is beset by issues such as uncertainties from ever-changing critical material attributes and strong coupling between variables in the multi-unit pharmaceutical tablet manufacturing process (PTMP), and how to timely adjust the operational variables to deal with such challenges has become a key problem in PQC. In this study, we propose a novel data-knowledge-driven modeling and operational adjustment framework for PTMP by integrating Bayesian network (BN) and case-based reasoning (CBR). At the modeling level, first, a distributed concept is introduced, i.e., the BN model for each subunit of PTMP is established in accordance with the operation process sequence, and the transition variables are given by the BN model established first and retrieved as the new query for the next unit. Once the BN models of all subunits are built, they are integrated into a global BN model. At the operational adjustment level, by taking the expected critical quality attributes (CQAs) and related prior information as evidence, the operational adjustment is achieved through global BN reasoning. Finally, the case study in a sprayed fluidized-bed granulation-based PTMP demonstrates the feasibility and effectiveness in improving the terminal CQAs of the proposed method, which is also compared with other methods to showcase its efficacy and merits.

CFD-DEM investigation of the gas-solid flow characteristics in a fluidized bed dryer

Wet granules drying in a fluidized bed is a complex process and the process involves heat and mass transfer between gas and solid phases as well as the moisture changes in the granules. CFD-DEM model was employed to investigate the wet granule flow characteristics, the heat and mass transfer process in a fluidized bed drying process. The proposed model considered the liquid bridge force varying with granule moisture content and was validated by experimental data. Due to the computational capability restriction, pseudo 2D model simulations were first employed for the whole drying process and then 3D model simulations were performed at certain moisture contents to investigate the flow dynamics in more detail. The effects of granule number and the changing liquid bridge force on the drying process were further analyzed. Granule agglomeration was generated in the drying process at high moisture content due to the liquid bridge force, which affects the fluctuations of pressure and bed height. Moreover, the heat and mass exchange between the gas and solid phases mainly occurred in the interface of bubble phase and granule phase. With the increase of bed height, the granule volume fraction decreased and the transfer coefficients between these two phases decreased.

Formulation, Development and Evaluation of Extended- Release Tablets of Carbamazepine

The current work sets out to design and develop a carbamazepine (CBZ) extended-release tablet in the treatment of epilepsy using wet granulation technology. The tablets were prepared using HPMC K 100M and ethyl cellulose as hydrophilic and hydrophobic polymers, respectively. The effect of the concentration of the polymer was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer. Tapped density, bulk density, angle of repose, Hausner's ratio, and Carr's index were all calculated for powder blends. The prepared trial batches of tablets were first characterized for hardness, friability, weight variation, and drug content to select an optimized batch. An in-vitro dissolution study of the optimized batch (F4) was carried out in distilled water using a USP Type I (basket type) dissolution apparatus at 100rpm. The optimized formulation (F4) showed a drug content of 99.51%. In-vitro drug release of optimized formulation was found to be 88.10% in 24hours. The optimised formulation demonstrated release for up to 24 hours. The optimised formulation's stability was studied for three months at 40±2ºC/75±5% RH, 30±2ºC/65±5% RH, and 25±2ºC/60±5% RH, and the prepared tablets showed no remarkable effect from the stability study. The results suggest that the developed extended-release tablets of CBZ (400 mg) could perform as therapeutically equivalent alternatives to conventional dosage forms, leading to better patient compliance.

Attribute transmission and effects of diluents and granulation liquids on granule properties and tablet quality for high shear wet granulation and tableting process

This study aims to examine (i) the effect of diluent types (lactose monohydrate, corn starch, and microcrystalline cellulose) and granulation liquids (20% polyvinylpyrrolidone K30, 65% alcohol, and dispersion containing 40% model drug– Pithecellobium clypearia Benth extracted powder) on granule properties and tablet quality for high shear wet granulation and tableting (HSWG-T) and, more importantly, (ii) the attribute transmission in the process. In general, the impact of diluents on granule properties and tablet quality was more dominant than that of granulation liquids. Attribute transmission patterns were revealed as follows. The granules’ ISO. Roundness and density correlated with raw material (i.e., model drug, diluent, and/or granulation liquid) properties such as density and viscosity. The granules’ compressibility parameter a correlated with the granules’ Span, and parameter y0 correlated with the granules’ flowability and friability. Compactibility parameters ka and kb correlated mainly with granules' flowability and density, and parameter b correlated significantly and positively with tablet tensile strength. The compressibility correlated negatively with tablet solid fraction (SF) and friability, while the compactibility correlated positively with tablet disintegration time. Moreover, the rearrangement and elasticity of granules correlated positively with SF and friability, respectively. Overall, this study provides some guides for achieving high-quality tablets via HSWG-T.