Moisture Activated Dry Granulation Research Articles

EVALUATION OF METRONIDAZOLE TABLETS FORMULATED WITH DIFFERENT DISINTEGRANTS USING MOISTURE ACTIVATED DRY GRANULATION

Introduction: Metronidazole is a synthetic oral nitroimidazole antibiotic used in the treatment of infections caused by anaerobic bacteria and protozoa. It also has amebicidal and antiprotozoal properties. Aim: The purpose of the study was to formulate and evaluate metronidazole tablets formulated with polymers (PVP and PEG) and maize starch as disintegrant using moisture activated dry granulation (MADG). Method: Twenty-four (24) batches of metronidazole granules and tablets were prepared by moisture activated dry granulation. Metronidazole (200 mg), lactose and gelatin (1, 2, 4, and 8 %) were mixed, followed by continuous mixing. Prior to compression, micro-crystalline cellulose, disintegrants and magnesium stearate were added. The dried granules were passed via 1.0 mm sieve after which they were labelled and stored in an air tight container. All other batches were also similarly prepared. Result: The result showed that the mean weight of the tablets ranged from 0.33±0.01 to 0.35±0.04 g. Tablet hardness ranged from 5.00±0.85 to 6.36±1.43. The results showed that batch 11 tablets had higher crushing strength than batch 24 with a significant difference. Table 2 shows the hardness test results and clearly indicates that the results of all the samples significantly differ from each other (p<0.05). The tablet friability test ranged from 0.21±0.17 for batch 24 and 0.60±0.16 for batch 11. The formulated tablets showed average disintegration time ranges from 0.52±0.01 to 14.03±0.03. According to USP, the disintegration time must be in the range of 15 min for uncoated tablets, and 30 mins for film coated tablets. Conclusion: The study established that polyethylene glycol and polyvinyl pyrrolidone polymers had better dissolution profile than maize starch which has the best disintegration properties. Peer Review History: Received: 4 March 2023; Revised: 26 April; Accepted: 20 June 2023, Available online: 15 July 2023 Academic Editor: Dr. Jennifer Audu-Peter, University of Jos, Nigeria, drambia44@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Julie Ann S. Ng, Blk 18 Lot 6 Grandville 3 Subdivision Mansilingan, Bacolod City, Philippines. julieann_ng@yahoo.com Dr. Essam Mohamed Eissa, Beni-Suef – 32 Tahrir St, Egypt, dressamceutics@yahoo.com

Evaluation of Metronidazole Tablets Formulated With Different Disintegrants Using Moisture Activated Dry Granulation (MADG)

Evaluation of Metronidazole Tablets Formulated With Different Disintegrants Using Moisture Activated Dry Granulation (MADG)

MOISTURE ACTIVATED DRY GRANULATION (MADG)

MOISTURE ACTIVATED DRY GRANULATION (MADG)

Study of Orally Disintegrating Tablets Using Erythritol as an Excipient Produced by Moisture-Activated Dry Granulation (MADG).

Moisture-activated dry granulation (MADG) is an eco-friendly granulation method that uses a small amount of water and insoluble excipients to absorb moisture. MADG is expected to improve productivity and reduce costs. Erythritol, an excipient used for preparing orally disintegrating tablets (ODTs), has poor tabletability and is difficult to form into tablets by conventional methods, such as high-shear granulation (HSG) and direct compression. In this study, we optimized the manufacturing conditions for ODTs to improve the tabletability of erythritol using MADG. The disintegration time of tablets made using the MADG method was approximately one-tenth that of those made using the HSG method, and the hardness was approximately 1.4 times higher. Moreover, MADG could delay disintegration and improve tabletability. We further attempted to optimize the manufacturing conditions using MADG, particularly in terms of the amount of water used. The disintegration time increased as the amount of added water increased. Moreover, water absorption tests revealed that capillary wetting decreased as the amount of water added increased, but the initial wetting did not change. These results suggested that the disintegration time was prolonged because of the increase in granule density and decrease in capillary wetting with the increase in the amount of added water. The hardness of the tablets increased because of the easy deformation of the granules after the addition of up to 3% water; however, when more than 3% water was added, the hardness decreased because of the aggregation of the granules with the excess water. Finally, two-dimensional maps of the effect of the amount of added water and water activity indicated that tablets with a hardness of ≥80 N and a disintegration time of ≤15 s could be produced by adjusting the amount of added water to within the range of 2.2–3.3% and water activity to 0.3–0.53. These results indicate that MADG can improve the tabletability of erythritol and be used for the granulation of ODTs. Tablets with appropriate hardness and disintegration properties can be produced by adjusting the water content to approximately 2.7% and the water activity to approximately 0.4 when producing ODTs with MADG.

Identification of Critical Factors Influencing the In-Vitro Dissolution o f Bicalutamide Tablets Prepared Using Madg Technique

This study was aimed to utilize the Moisture Activated Dry Granulation (MADG) technique to formulate Bicalutamide tablet and identify critical factors influencing its dissolution. The Bicalutamide inclusion complex was formed using the kneading method. Aeroperl 300 was selected as an adsorbent, polyvinylpyrrolidone (PVP) K30 as a binder, Microcrystalline Cellulose (MCC) and Lactose Monohydrate (LMH) in1:1 ratio as fillers. Croscarmellose sodium (CCS) and neusilin were used as disintegrating agents, as they did not affect the disintegration time when hardness and compression force increased. Box Behnken experimental design was used to optimize formulations and was evaluated for pre and post-compression parameters. The optimized formulation was compared with the marketed and wet granulation formulation. In addition, the short term stability testing of the optimized batch was performed. The optimized inclusioncomplex of hydroxypropyl beta-cyclodextrin (HP-ß-CD) was selected based on a phase solubility study in 1:1 ratio with drug toimprove solubility. The optimized batch was prepared by MADG at granulator speed of 540rpm, using 4.30 % PVPK30, and 1.5 % Aeroperl 300. It showed a disintegration time of 208.33 sec.Percentage drug release was 95.02 % in 30 mins, and hardness 5.4 kg/cm2. The stability study results confirmed the stability of the tablets. The Bicalutamide tablet was successfully formulated using the MADG technique. The parameters affecting the in-vitro dissolution were identified and optimized, leading to better bioavailability. Keywords: Bicalutamide, Moisture Activated Dry Granulation technology (MADG), hydroxypropyl beta-cyclodextrin (HP-β-CD), Box Behnken design (BBD), Croscarmellose sodium

Enhancing the Poor Flow and Tableting Problems of High Drug-Loading Formulation of Canagliflozin Using Continuous Green Granulation Process and Design-of-Experiment Approach.

Maximization of drug-loading can significantly reduce the size of dosage form and consequently decrease the cost of manufacture. In this research, two challenges were addressed: poor flow and tableting problems of high-drug loading (>70%) formulation of canagliflozin (CNG), by adopting the moisture-activated dry granulation (MADG) process. In this method, heating and drying steps were omitted so, called green granulation process. A 32 full-factorial design was performed for optimization of key process variables, namely the granulation fluid level (X1) and the wet massing time (X2). Granulation of CNG was carried out in the presence of polyvinylpyrrolidone, and the prepared granules were compressed into tablets. Regression analysis demonstrated the significant (p ≤ 0.05) effect of X1 and X2 on properties of granules and corresponding tablets, with pronounced impact of X1. Additionally, marked improvement of granules’ properties and tableting of CNG were observed. Furthermore, the optimized process conditions that produced good flow properties of granules and acceptable tablets were high level of granulation fluid (3.41% w/w) and short wet massing time (1.0 min). Finally, the MADG process gives the opportunity to ameliorate the poor flow and tableting problems of CNG with lower amounts of excipients, which are important for successful development of uniform dosage unit.

Design, Optimization, and Correlation of In Vitro/In Vivo Disintegration of Novel Fast Orally Disintegrating Tablet of High Dose Metformin Hydrochloride Using Moisture Activated Dry Granulation Process and Quality by Design Approach.

Compression of cohesive, poorly compactable, and high-dose metformin hydrochloride into the orally disintegrating tablet (ODT) is challenging. The objective of this study was to develop metformin ODT using the moisture activated dry granulation (MADG) process. There are no reports in the literature regarding the development of ODT based on MADG technology. The feasibility of developing metformin ODT was assessed utilizing a 32 full factorial design to elucidate the influence of water amount (X1) and the amount of pregelatinized starch (PGS; X2) as independent variables on key granules and tablets’ characteristics. The prepared granules and tablets were characterized for granule size, bulk density, flow properties, tablets’ weight variation, breaking force, friability, capping tendency, in vitro and in vivo disintegration, and drug release. Regression analysis showed that X1 and X2 had a significant (p ≤ 0.05) impact on key granules and tablets’ properties with a predominant effect of the water amount. Otherwise, the amount of PGS had a pronounced effect on tablet disintegration. Optimized ODT was found to show better mechanical strength, low friability, and short disintegration time in the oral cavity. Finally, this technique is expected to provide better ODT for many kinds of high-dose drugs that can improve the quality of life of patients.

Importance of free water in controlling granule and tablet properties in a novel granulation method, green fluidized bed granulation (GFBG).

In the pharmaceutical field, green fluidized bed granulation (GFBG) is a novel and eco-friendly manufacturing technology used to produce desired granules via simple blending and spraying steps at ambient temperature using a standard fluidized bed granulator. However, the relations between water content and granule and tablet qualities have not yet been elucidated for GFBG. The purpose of this study was to elucidate the influence of different water quantities used in the GFBG process on granule and tablet qualities. In addition, results from the GFBG process were compared with those from the moisture-activated dry granulation (MADG) process. In terms of tablet tensile strength and disintegration time, GFBG had a wider acceptable range for added water quantity (2.0-5.0%) than did MADG. For all added water quantities, the GFBG granules were within the upper limit of water activity (a surrogate of free water amount), which was 0.61 for tensile strength and 0.55 for disintegration time. The air flow in the GFBG process may have reduced the excess free water on the granules during the absorption process. It was concluded that as compared with MADG, GFBG may be a more robust process for manufacturing granules and tablets with superior properties.

Novel, lean and environment-friendly granulation method: Green fluidized bed granulation (GFBG)

The Green fluidized bed granulation (GFBG) technology is based on the moisture activated dry granulation (MADG) technique and consists only of a mixing and a spraying process using a fluidized bed granulator, requiring no heating process. This provides a less energy-consuming and environment-friendly granulation method compared to current fluidized bed granulation (FBG) and high-shear granulation (HSG) methods. The aim of this study is to compare and evaluate the manufacturability, and granule and tablet properties among GFBG, MADG, FBG and HSG.The GFBG process time took less than 20 min for producing final blends at a 700 g scale, which was comparable to MADG. This process time was significantly shorter than that of FBG and HSG. GFBG not only had the shortest process time but also reduced the number of manufacturing machines compared to FBG and HSG.The Hausner ratio (HR) of granules from GFBG (1.30) indicated a good flowability, and no problems were observed in the tablet mass variability during compression.Tablets produced using GFBG achieved sufficient tensile strength (>1.5 MPa) even at a low compression force and demonstrated the fastest disintegration time compared to the other manufacturing methods. Tablet disintegration is related to wettability and porosity, therefore the tablet wettability (initial and capillary wetting) and tablet porosity were investigated. As a result, the capillary wetting of the tablets produced using GFBG was 3.6 times higher than the tablets produced using FBG, which might have affected the fast disintegration of the tablets produced using GFBG.

TABLET GRANULATION: CURRENT SCENARIO AND RECENT ADVANCES

Granulation is a size enlargement process, in fine or coarse particles converted into physically stronger and larger agglomerates having good flow property, better compression characteristics and uniformity, prevent segregation of the blend components, improve content uniformity, and eliminate excessive amounts of fine particles. Size of granules has a size range of 0.2 to 4.0 mm, depending on their subsequent use. Size of the granules depends on the quantity and feeding rate of granulating liquid. The selection of process to prepare granules requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, to name a few. At current scenario available technologies includes, spray drying, roller compaction, high shear mixing, and fluid bed granulation etc. The objective of present work is to focus on the commonly used and novel granulation technologies like such as pneumatic dry granulation, steam granulation, moisture-activated dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or foam granulation. Peer Review History: Received 1 September 2017; Revised 5 October; Accepted 4 November, Available online 15 November 2017 Academic Editor: Dr. Sally A. El-Zahaby, Pharos University in Alexandria, Egypt, sally.elzahaby@yahoo.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 3.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Dr. Francis Adou Yapo, Felix Houphouet Boigny, University of Abidjan, Ivory Coast, fyapo@yahoo.fr Dr. Hebatalla Ibrahim Ahmed Abdel Hameed, Al-Azhar University, Faculty of Pharmacy (Girls), Nasr City, Cairo, Egypt, hebatalla123@yahoo.com Similar Articles: IN VITRO-IN VIVO BIO-EQUIVALENCE CORRELATION STUDY OF ATENOLOL, AND ITS BRANDS OF IMMEDIATE RELEASE TABLET UNDER BIO-WAIVER CONDITIONS

Application of moisture activated dry granulation (MADG) process to develop high dose immediate release (IR) formulations

Moisture activated dry granulation (MADG) method was used to develop IR tablets with cohesive, fluffy and high dose drugs. To evaluate this approach, three drugs: metformin hydrochloride, acetaminophen and ferrous ascorbate were selected as model compound along with three binders: maltodextrin DE16, PVP K 12 and HPC. The granules were generated using MADG method and tablets were prepared using rotary tablet press. The granules and tablets were characterized for particle size analysis, flow properties, tablet hardness, friability, moisture content, dissolution study, disintegration time and stability study. All results were found to be within acceptable limits. Development of all formulation tablets were found as best fitted for an immediate release of Metformin hydrochloride, acetaminophen and ferrous ascorbate. MADG delivered a robust manufacturing process for generation of granules with excellent flowability. The tablets prepared using this method were found to show better content uniformity, good compactability and low friability. Use of this approach aids to lower the amount of excipients used to overcome physiochemical limitation of the drug substances and there side effects. Both drying and milling steps in wet granulation were not required for MADG process. MADG became a cost effective process which could lead to reduced total tablet size and also save time.

NOVEL TECHNIQUES OF GRANULATION: A REVIEW

Granulation is an important unit process in the production of pharmaceutical dosage forms like tablets, capsules and other do sage forms. Granulation process increases flow, compressibility and content uniformity of the powders. It inhibits the separation o f blend components and reduces excessive amount of fine particles. This process helps to achieve improved yields with less tablet manufacturing defects. Particle size of granules depends on the quantity and feeding rate of the granulating liquid. Selecting a method of granulation requires comprehensive study of each ingredient in the formula, the combination of ingredients and their compatibility with each other is checked after, which appropriate granulation proces s can be applied. The recent technologies used for granulation include steam granulation, moisture activated dry granulation (MADG), moist granulation technique (MGT), extrusion - spheronization granulation , fluidized bed granulation, thermal adhesion granulation process (TAGP) and foam granulation etc. have their own advantages and overcome the disadvantages of conventional granulation process such as dust generation or deteriorating ef fect of heat as drying step. The objective of present work is to focus on the novel granulation technologies.

The effect of water activity on granule characteristics and tablet properties produced by moisture activated dry granulation (MADG)

This study evaluated the effects of changing the amount of added water for moisture activated dry granulation (MADG) on the resulting granule characteristics and tablet properties. Water soluble fillers and binders were pre-mixed in a granulator, and the binder was activated by a small amount of water to form granules. The amount of added water was defined as the percentage of granulation water by mass to charged powder. Granules made with 0.0%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, and 5.0% (w/w) added water were evaluated in this study. Furthermore, the effect of free water content on tablet characteristics was investigated by measuring water activity.The Hausner ratio (HR) of MADG granules is significantly decreased by increasing the amount of added water up to 1.0% (water activity over 0.39). However, the HR of MADG granules did not change with further increase in water activity (added water over 2.5%). The free water content (water activity over 0.61, water added over 2.5%) may reach a limit in improving the flowability of MADG granules.MADG tablet tensile strength was increased along with the increased water activity when the added water amount was from 0.0% to 2.5%. However, MADG tablet tensile strength prepared with 3.0% or 5.0% added water was lower than in other tablets. Similarly, MADG tablet tensile strength was increased with increasing water activity from 0.0% to 2.5% added water. Yet, the magnitude of the negative slope between 2.5% and 5.0% added water was approximately ten times greater compared to the magnitude of the slope between 0.0% and 2.5% added water. By increasing the amount of added water over 2.5%, the excess amount of free water may have caused the decreasing tensile strength of the MADG tablets.MADG tablet initial wetting was correlated with water activity, and free water content was shown to have significant impact on the initial wetting of MADG tablets. Furthermore, this association between free water content and initial wetting of MADG tablets had a significant impact on tablet disintegration. Free water content had a low or minor impact on tablet porosity and capillary wetting.

Granulation techniques and technologies: recent progresses.

Granulation, the process of particle enlargement by agglomeration technique, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. Granulation process transforms fine powders into free-flowing, dust-free granules that are easy to compress. Nevertheless, granulation poses numerous challenges due to high quality requirement of the formed granules in terms of content uniformity and physicochemical properties such as granule size, bulk density, porosity, hardness, moisture, compressibility, etc. together with physical and chemical stability of the drug. Granulation process can be divided into two types: wet granulation that utilize a liquid in the process and dry granulation that requires no liquid. The type of process selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, to name a few. Among currently available technologies, spray drying, roller compaction, high shear mixing, and fluid bed granulation are worth of note. Like any other scientific field, pharmaceutical granulation technology also continues to change, and arrival of novel and innovative technologies are inevitable. This review focuses on the recent progress in the granulation techniques and technologies such as pneumatic dry granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or foam granulation. This review gives an overview of these with a short description about each development along with its significance and limitations.

Application of a convenient and cost‑effective granulation technology for the formulation of tablets using conventional excipients

In the present investigation, suitability of a cost‑effective and convenient granulation technique that is, moisture activated dry granulation (MADG) process for high drug loading in tablet formulation was studied. In this work, effect of the amount of water on flow properties of granules as well as an effect of mixing time on surface morphology of granules was studied. Paracetamol (PCM) immediate release granules were prepared using conventional excipients such as polyvinylpyrrolidone K‑30, Kollidon VA 64 (as binders), and simple equipments by MADG technique. The prepared granules were evaluated for flow properties and tablets were compressed using optimized granule formulation. The prepared granules possessed good flow properties that is, angle of repose was 32.11 and percent compressibility index was 19.44. Tablets disintegrated in 2.08 min and 89% of the drug was released within 30 min. All the results were comparable with PCM tablets prepared by wet granulation method. Therefore, from the above studies it was concluded that MADG process may be effectively adopted by using Kollidon VA 64 as a binder in tablet formulations where high drug loading is to be achieved, where all the parameters of the formulation can be obtained within specified limits using this simple, convenient, less time consuming, economical, and efficient method of granulation. Key words: Moisture activated dry granulation, paracetamol, precompression parameters and postcompression parameters, wet granulation

Importance of excipient wettability on tablet characteristics prepared by moisture activated dry granulation (MADG)

For moisture activated dry granulation (MADG), microcrystalline cellulose (MCC) or silicon dioxide is recommended for the moisture absorption stage. The aim of this study was to assess the suitability of alternative excipients as moisture absorbents with regard to the disintegration mechanism of resulting lactose based placebo formulations. Beside high and low moisture MCC grades, the additions of magnesium aluminometasilicate (MAMS), pregelatinized starch (S1500), crospovidone (Kollidon CL) and carmellose calcium (ECG 505) were evaluated. High shear granulation (HSG) was conducted as a reference process. The overall disintegration time of all tablets produced by MADG was significantly faster whereas hardness yield and mass-variability were equal or superior compared to the HSG process. Powder wettability of the different moisture absorbents was identified to be a key driver for rapid disintegration, whereas tablet porosity had only a minor influence on the target hardness of the tablets.

Excipient-Excipient Interaction in the Design of Sustained-Release Theophylline Tablets: In Vitro and In Vivo Evaluation

Sustained-release (SR) theophylline (TPH) tablets were prepared by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29–31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%–4.2%), depending on SAL:CG ratios. The corresponding tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). The release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for Quibron. The in vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for up to 24 h. The formulated tablets showed 104.65% bioavailability relative to that of the commercial tablets. The rate and extent of absorption of TPH showed no significant differences from that of the commercial tablets. Moreover, no significant differences were found in the pharmacokinetic parameters related to the rate and extent of TPH absorption from the prepared and commercial tablets.

Moisture-Activated dry Granulation in a high Shear Mixer

AbstractThe applicability of a 25 litre high shear mixer for moisture-activated dry granulation was examined. Microcrystalline cellulose, potato starch or a mixture of 50% m/m of each was used as moisture absorbing material. The effects of water content, wet massing time, moisture absorbing material and dry mixing time on the size distribution, and the compressibility of the granulations were investigated. Tablets were compressed on a single punch press from all the granulations and on a rotary press from a few of the granulations.It was shown that the physical properties of the tablets were primarily affected by the water content, the moisture absorbing material, and the compression force. Tablets with low mass variation, high crushing strength, low friability, and short disintegration time were achieved with both tablet presses by using a mixture of microcrystalline cellulose and potato starch as moisture absorbing material.

Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets

During the development of a tablet formulation of a cohesive, fluffy investigational drug, a novel moisture-activated dry granulation (MADG) process was studied in comparison with two conventional granulation methods, i.e., wet granulation and dry granulation with a roller compactor, as well as with a direct compression formulation method. The MADG method produced granules with excellent flowability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. The tablets prepared using the MADG method had better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes