Granulating Fluid Research Articles

Metallic aluminium in municipal solid waste incineration fly ash as a blowing agent for porous alkali-activated granules.

Porous alkali-activated materials are synthetic aluminosilicates that should be often produced as granules for practical applications. In the present study, municipal solid waste incineration fly ash with ~1.2 wt% of metallic aluminium was used as a novel blowing agent for metakaolin (their ratio ranged from 0% to 100%) with an aqueous sodium silicate solution as the alkali-activator and granulation fluid in high-shear granulation. The compressive strength of all granules was sufficient (≥2 MPa). Water absorption indicated an increase in porosity as the fly ash content increased. However, X-ray microtomography imaging showed no clear correlation between the fly ash content and porosity. The granules exceeded the leaching limits for earth construction materials for antimony, vanadium, chloride and sulphate. Of those, antimony, chloride and sulphate could be controlled by decreasing the ash content, but the source of vanadium was identified as metakaolin. The increase in the fly ash content decreased the cation exchange capacity of the granules. In conclusion, the recommended fly ash content is equivalent to 0.3 wt% of Al0 and the developed granules could be best suited as light-weight artificial aggregates in concrete where the additional binder would provide stabilization to decrease the leaching.

Preparatiοn οf pοrοus hydrοxyapatite-metakaοlin geοpοlymer granules fοr adsοrptiοn applicatiοns using pοlyethylene glycοl as pοrοgen agent and sοdium dοdecyl sulfate as aniοnic surfactant.

This study investigated the elaboration of novel porous absorbent granules by mixing powdered hydroxyapatite, metakaolin, sodium metasilicate, polyethylene glycol, and sodium dodecyl sulfate (SDS), an anionic surfactant. The effect of sodium dodecyl sulfate (SDS) was then studied by introducing it as a powder to the powdered mixture or dissolved into the granulation fluid. Characterization of the granules indicated that the incorporation of SDS dissolved in the granulation fluid into the G-PEG granules improved their specific surface area (97.9 m2/g) and porosity, resulting in a synergistic increase in the adsorption of crystal violet and methylene blue dyes compared to G-PEG granules and hydroxyapatite or metakaolin geopolymer alone. Moreover, the granules exhibited satisfactory compressive strength of 0.81MPa, making them suitable for large-scale adsorption columns. Finally, the regeneratiοn prοcess οf the granules was modeled and optimized by using surface response methodology based on Box-Behnken design. The granules cοuld be regenerated fοr eight cycles under οptimum cοnditiοns οf acetic acid cοncentratiοn οf 0.72 mοl/L, a temperature οf 323K, and a cοntact time οf 173.22min, withοut a significant lοss in the adsοrptiοn capacity οr degradatiοn οf the granules. These results suggest that the pοrοus granules prepared in this study have pοtential tο be used in industrial wastewater treatment.

Optimization of ticagrelor tablet for gastro-retentive drug delivery using full factorial design

Purpose: To identify the optimized region of formulation using quality by design for developing ticagrelor gastro-retentive (GR) tablets. 
 Methods: A 23 + 3 full factorial design of experiments study was used to identify three factors (polyethylene oxide (PEO), compression, and volume of granulating fluid) involved in the wet granulation and compression process of ticagrelor GR tablets. Hardness, friability, content, dosage unit uniformity, and pH 1.2 dissolution rate (at 4, 8, and 12 h) were evaluated as critical quality attributes via analysis of variance using Design Expert software. 
 Results: All seven models were significantly influenced based on analysis of variance results (p < 0.05). Hardness and friability were significantly affected by compression (p < 0.0001). Content uniformity was significantly affected by the interaction between compression and granulating water volume for wet granulation (p < 0.05), and dosage unit uniformity was significantly affected by the volume of granulating fluid for wet granulation (p < 0.05). However, all results were within acceptable ranges. Polyethylene oxide (PEO) (4 h, p < 0.05; 8 h, p < 0.05; 12 h, p < 0.05) and compression (4 h, p < 0.05; 8 h, p < 0.05; 12 h, p < 0.05) had negative effect on pH 1.2 dissolution rate. 
 Conclusion: Design of experiment (DoE) approach has been used to optimize region of PEO, compression, and volume of granulating fluid for formulation development. This outcome is expected to be a basis for further research to develop TCG GR tablets on a large production scale.

Porous metakaolin geopolymer as a reactive binder for hydroxyapatite adsorbent granules in dye removal

In this study, porous hydroxyapatite-metakaolin geopolymer (HAP-MK-GP) granules were prepared with a novel method for adsorption of organic pollutants from aqueous solutions, using brilliant green dye as a model compound. The preparation involved combining finely powdered hydroxyapatite, metakaolin, and solid sodium metasilicate in a high-shear granulator. Then, hydrogen peroxide (H2O2) was added at different concentrations (0.0, 5.0, 7.5, or 10.0%) as a combined granulation fluid and blowing agent. In the resulting granules, metakaolin geopolymer bound the powdered hydroxyapatite as granules and contributed to the adsorption capacity. To determine their structural, morphological, and mechanical properties, the granules were characterized with infrared spectroscopy, X-ray fluorescence, scanning electron microscopy, specific surface area and porosity analysis, and compressive strength tests. The granules had a high porosity and promising compressive strength and Young's modulus of 0.8 and 10 MPa, respectively, potentially enabling their use in large-scale adsorption columns. The monolayer adsorption mechanism of brilliant green dye onto HAP-MK-GP granules was confirmed by fitting the obtained batch adsorption data to the Langmuir isotherm model which showed that the adsorption capacity was approximately 41 mg/g. The optimum conditions were: pH of 7, initial dye concentration of 100 mg/L, adsorbent dose of 3 g/L, agitation speed of 250 rpm, contact time of 30 min, and temperature of 298 K. The adsorption kinetic data indicated that the adsorption followed the pseudo-second-order kinetic model. The thermodynamic parameters, including Gibbs free energy, enthalpy, entropy, and activation energy, indicated that adsorption was spontaneous, endothermic, and was based on physisorption. The rate-limiting step was film diffusion. Based on the results, HAP-MK-GP granules could be a feasible adsorbent for the removal of dyes from industrial wastewater. Moreover, the facile granulation method presented here could be applied to other powdered adsorbents as well to prepare adsorbent granules.

Combined granulation–alkali activation–direct foaming process: A novel route to porous geopolymer granules with enhanced adsorption properties

High-value applications, such as adsorbents, have drawn attention to geopolymers. In several of those applications, having the geopolymer as porous spherical particles is beneficial. This study presents a novel process for fabricating porous metakaolin-based geopolymer granules using a combination of direct foaming, one-part alkali activation, and granulation. In short, the precursor (e.g., metakaolin) and solid activator (e.g., sodium silicate) are loaded in a granulator, in which an aqueous blowing agent (e.g., H2O2) is added while the granulator is running, and the obtained granules are cured at 60 °C. Characterization of the granules for physico-chemical and morphological properties indicated an increase in overall porosity, especially in the µm-scale pores. Also specific surface area (+50%) and nanoscale pore volume (+102%) increased when using more concentrated H2O2 (20 or 30%) compared to nonporous granules. The use of porous granules was also demonstrated in dynamic adsorption experiments for ammonium (NH4+) uptake, which showed up to ∼126% increase in cumulative adsorption amount compared to nonporous granules. The highest NH4+ uptake was obtained with 10% H2O2 solution as the granulation fluid. The results confirmed the feasibility of the method for introducing porosity to geopolymer granules, which enhances the adsorption properties of the granules.

Osmotic release tablets formulation and evaluationof ace inhibitor molecule

In the present study the Suitable analytical methods were developed for the drug using UV – visible spectrophotometer. From the Preformulation study and thermal analysis (DSC), the interference was verified and found that the drug did not interfere with the excipient use.Core tablet was successfully prepared by wet granulation using Polyethylene oxide WSR N80, Mannitol 25C, silicon dioxide, magnesium stearate, Polyethylene WSR 303, sodium chloride, hydroxypropyl methylcellulose (HPMC E5), Iron oxide red. Isopropyl cellulose was found to be suitable granulating fluid for binder.Formulation of the drug coating was optimized by using 22 factorial design of experiment.The coated tablets were evaluated for various physicochemical parameter. About 79 to 95% of drug was released from the formulation A-E in 24 hr in 6.8 phosphate buffer.The in vitro drug release data were plotted in zero order kinetics and optimized batch were evaluated on the basis of regression coefficient.The in-vitro drug release from the optimized formulation in the dissertation was directly proportional to the concentration of plasticizer and concentration of cellulose acetate.The manufacturing procedure was standardized and reproducible

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.

Preparation and in vitro characterization of carvacrol pellets by combination of liquisolid technique and extrusion-spheronization

ObjectiveCarvacrol is one of the main pharmacologically active components of Thymus vulgaris essential oil, which has shown several therapeutic effects. Because of liquid nature of the carvacrol, the formulation of the drug is challenging. Liquisolid technique is a method for converting a liquid drug into a solid system. The aim of this study is to combine the liquisolid approach and extrusion-spheronization technique to produce pellets with desirable physico-mechanical, stability and release properties. MethodsThree different methods were used for preparation of liquisolid matrix of carvacrol using PVP K30, stearic acid and Aerosil. The matrices were utilized for preparation of pellets by extrusion-spheronization method. The pellets were characterized for size (sieve analysis), shape factors (image analysis), mechanical strength, chemical interactions (FTIR), thermal behavior (DSC), carvacrol content, release rate (dissolution test) and stability. ResultsThe results showed that by using suitable composition of liquisolid matrix and granulation fluid, pellets with desirable size and shape and mechanical properties could be produced. PVP-based pellets had higher mechanical strength, slower release rate and improved content and stability compared to stearic acid or Aerosil-based pellets. The carvacrol ratio has considerable effect on release properties of the pellets. ConclusionOverall results revealed the feasibility of preparing desirable pellets containing carvacrol with acceptable content, stability and release properties, which can be administered as hard gelatin capsules. PVP-based pellets were the most appropriate formulation according to evaluation tests.

LIQUISOLID-PELLETS TECHNIQUE: A RECENT TECHNIQUE FOR ENHANCING SOLUBILITY AND BIOAVAILABILITY OF DRUGS

The current article aims with the introduction of newer solubility enhancing technique as Liquisolid-pellet. The majority of newly invented molecules comes under the biopharmaceutical classification system (BCS) Class II, IV indicating poor solubility and thereby poor bioavailability. Liquisolid Compaq is one of the solubility enhancement techniques used for improving solubility and dissolution of the molecule by incorporating non-volatile solvent followed by carrier and coating agents. However, this technique is only applicable to potent molecules as a higher dose resulted in inconvenience to the patient and difficult to swallow. Another drawback of this method is not suitable for pilot plant scale-up. Liquisolid pellet technique overcoming all limitations of Liquisolid Compaq and offers good compaction, flowability, dose accuracy, less gastric irritations, and better bioavailability. In the Liquisolid-Pellet technique, powdered material received from Liquisolid Compaq is further moistened with granulating fluid to provide enough plasticity. The material is subjected to extrusion using an extruder to generate extrudates. The extrudates are placed under the spheronizer to form spherical particles as Pellets. The pellets are mainly prepared by extrusion-spheronization and hence, articles elaborate details of extruders and spheronizers, their specifications as well as factors, which strongly impart processing. These pellets are filled in capsules according to their dose and utilized as an immediate release or sustained release. The literature related to this review was collected from Science Direct, PubMed, Google Scholar, Google, USPTO, etc. from 1998 to 2020 with the following key-words.

Rheological behavior of porous pharmaceutical materials: Linking torque profiles during wet massing to water diffusion coefficients and penetration time

Wet massing is commonly performed during the wet granulation process after the addition of a liquid binder. Torque values were measured using a Mixer Torque Rheometer (MTR) by the method of multiple additions of water and variable mixing time. The main objective of this work is to link water diffusion coefficients and penetration time in pharmaceutical powders to torque profiles generated in an MTR. The diffusion coefficients were calculated by fitting the experimental data to an exponential decay function and by minimizing the Root Mean Square Error between the fitted curve and the solution of Fick’s 2nd law. Water penetration times were measured and calculated using experimental drop penetration and Washburn methods, respectively. The main research hypothesis is that the temporal change in torque profiles after each water addition step is related to the mass diffusion coefficients and water penetration time in the powder of varying degrees of water content. The results show that for the microcrystalline cellulose (MCC) powders at varying granulating fluid levels, capillary diffusion seems to be more adequate to explain the rheological behavior observed compared with the Fickian diffusion model.

Formulation and Evaluation of Combination Tablet of Anti-Hypertensive and Diuretic Drugs

The primary aim of this development is to have a stable formulation of antihypertensive and Diuretic drugs. Oral drug delivery system is the most convenient and easiest route of administration. We are going to make tablet dosage form in combination of two drugs i.e one is antihypertensive and another is diuretic drug. Formulation of tablet content API (active pharmaceutical ingredient) and different excipient like diluent, need of diluent to increase the bulk of tablet if we have use low-dose of drug, binder, disintegrant and lubricant. The Telmisartan and Hydrochlorothiazide Tablets will prepare by using low substituted disintegrant. The addition of Diuretics to angiotensin II receptor blockers will potentiate the action of angiotensin receptor blockers. The tablets are prepared by using wet granulation technology and purified water is used as a granulating fluid And evaluation of tablet by using different parameter like weight variation , friability, tablet size and thickness and hardness testing ,disintegration test and dissolution testing.

Water-soluble and -insoluble polymers as binders for pellet preparation by extrusion/spheronization

The objective of this study was to investigate the effect of binder (water-soluble vs. -insoluble) and granulation fluid (aqueous vs. organic) on the physical properties of pellet prepared by extrusion/spheronization and on drug release. Size distribution, sphericity, bulk density, crushing force and swellability of the pellets were investigated. Pellets prepared with isopropanol (IPA):water as a granulation fluid were less dense and weaker than those prepared with water. The pellets prepared with water as the granulation fluid demonstrated higher swelling than those prepared with IPA:water irrespective of the drug loading and binder content. To achieve release retardation, pellets were coated with ethylcellulose (EC) having a thickness according to the drug solubility, except those contained carbamazepine. When IPA:water was used as a granulation fluid instead of water, carbamazepine release increased and propranolol HCl release decreased. Pellets prepared with hydroxypropyl methylcellulose (HPMC) as the binder swelled and damaged the thin EC coat that resulted in a fast release. Hence, to avoid higher coating level, EC of higher molecular weight was used. It is concluded that binder type and granulation fluid had a great impact on physical properties and drug release from pellets prepared by extrusion/spheronization.

Effect of Acupuncture Combined with Gavage of Rule Granule on Serum Prolactin, Estradiol and Progestone Contents and Their Receptor Expression in Breast in Mammary Gland Hyperplasia Rats

To observe the effect of acupuncture combined with medication (Rule Granule) on serum prolactin (PRL)，estradiol (E2) and progestone (P) contents and expressions of prolactin receptor (PRLR), estrogen receptor (ER) and progestrone receptor (PR) proteins in mammary gland (MG) tissues of MG hyperplasia (MGH) rats, so as to explore its mechanisms underlying improvement of MGH. A total of 55 female SD rats were randomized into blank control group (n＝10), model group (n＝10), acupuncture group (n＝11), medication group (n＝10), and acupuncture plus medication group (n＝9). The MGH model was established by muscular injection of E2 benzoate(0.5 mg/kg, once daily for 20 days), followed by injection of P (5 mg/kg) into the lateral muscle of the hind-limb, once daily for 5 days, and the rats of the control group were treated by muscular injection of normal saline at the same site and in the same procedures. Acupoint group A composed of bilateral Tianzhong (SI 11), Ganshu (BL 18) and Zusanli (ST 36), and group B composed of Tanzhong (CV 17), and bilateral Wuyi (ST 15) and Hegu (LI 4) were alternatively punctured with filiform needles and stimulated swiftly by twirling the needle in each acupoint for 20－30 sec, once daily for 30 days. Rats of the medication group and acupuncture ＋medication group were treated by gavage of Rule Granule fluid containing Baishao (Paeonia Iactiflora Pall), Danggui (Angelica sinensis), etc. (1.5 mL/100 g for each rat) and those of the other groups treated by gavage of distilled water (1.5 mL/100 g). The treatment was given once daily for continuous 30 d. At the end of the experiments, the rats' abdominal aorta blood was collected for assaying the contents of serum PRL, E2 and P with ELISA, and the pathological changes of breast tissue (the left 2nd pairs) were observed under microscope after sectioning and H．E. staining. The expression of PRLR, ER and PR proteins in the breast tissue was detected by immunohistochemistry. After modeling, the hyperplasia of mammary gland in the model group was obvious; the serum PRL and E2 contents and the immunoactivities of PRLR, ER and PR were significantly increased (P<0.01); and the content of serum P was considerably decreased in the model group in comparison with the blank control group (P<0.01). After the treatment, the hyperplasia of mammary gland was improved; the serum PRL and E2 contents and the expression of PRLR, ER and PR were significantly decreased (P<0.05, P<0.01); and the content of P was notably increased in the acupuncture, medication and acupuncture plus medication groups relevant to the model group (P<0.05，P<0.01). The therapeutic effects of acupuncture plus medication were significantly superior to those of both simple medication and simple acupuncture in down-regulating serum PRL and E2 contents and PRLR, ER and PR immunoactivity, as well as in up-regulating serum P content (P<0.05). No significant differences were found between the medication and acupuncture groups in the above mentioned 3 serum and 3 mammary indexes (P>0.05)．. Acupuncture, Rule Granule, and acupuncture combined with Rule Granule can improve hyperplasia of mammary gland in rats, which may be related to their effects in reducing serum PRL and E2 and breast ER, PR and PRLR expression levels, and in increasing serum P level. The therapeutic effects of acupuncture plus Rule Granule are better than those of simple acupuncture and simple Rule Granule.

Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator

The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (∼0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre-blending step.

Algal Nanosuspensions for Dermal and Oral Delivery

Background: Algae are widely used for their beneficial properties by food, cosmetic and nutraceutical industry. For nutraceutical and cosmetic (e.g. oral and dermal) application, solubility is a key parameter. Algal extracts are available in sticky and completely dried form and in both cases it is difficult to formulate them due to solubility challenges. Therefore, attempts were made to produce stable algal nanosuspensions. A nano algal suspension could increase the biological activity (due to increased saturation solubility and higher dissolution velocity) and lead to better penetration or absorption profile. Methods: Dried algae products (N. oculata and Chaetoceros) were obtained from biotechnological cultivation. The algae were dispersed in Tween 80 or in Poloxamer 188 solutions and passed through a piston-gap high pressure homogenizer to produce nano algal suspensions. Production parameters like, number of homogenisation cycles, pressure etc, were optimised. Nanosuspensions were evaluated for particle size, zeta potential and crystallinity. Furthermore, nanosuspensions were converted to solid product using lyophilisation and extrusion-spheronisation technique. Results: A minimum size of about 226 nm could be achieved after 10 cycles at 1,500 bar. The aqueous nanosuspensions showed highest, but still insufficient stability at refrigeration (4 months data), decreasing stability with increasing temperature, especially at 50°C in the stress storage test and during autoclaving at 121°C. Preservation with Euxyl PE 9010 further decreased the physical stability of the aqueous algae nanosuspensions. Algae as natural material undergoes chemical degradation when in contact with water. For long-term preservation of the size and for chemical stabilization, the algae nanosuspensions were lyophilized. The algae nanoparticles re-dispersed well in water when using trehalose as cryoprotectant. The lyophilizate can be filled in capsules. Pellets were produced using the nanosuspensions as granulation fluid, filled in gelatine capsules for nutraceutical delivery. Conclusion: Nano-algal suspensions open new perspective for algae products with enhanced bioavailability and penetration profile. The produced nanosuspensions can be used for dermal, nutraceutical or cosmetics purposes. Keywords: Algae, N. oculata, Chaetoceros, nanocrystals, dermal application, oral delivery, nutraceutical, nanonisation, nanosupensions.

Microstructure of micro-crystalline cellulose based granules produced by high-shear wet granulation with long wet-massing time

Design and scale-up of batch high-shear granulation is complicated by the interplay of granule nucleation, growth, and breakage and their non-linear dependence on liquid binder addition rate and granulation time. In an earlier paper, we demonstrated that during extended wet massing times, granule growth and breakage rates become equal (pseudo-steady-state granulation), and the ultimate granule size distribution depends only on agitation intensity and granulating fluid level. This significantly simplifies scale-up. The granule size distributions produced in these long granulation times were quite narrow compared to those produced in more typical granulation times.This work provides additional characterization of the granules produced in “steady-state” granulation. We observe an interesting microstructural change in granules comprised of microcrystalline cellulose and lactose. During extended wet massing, these granules evolve from typical agglomerates comprised of primary MCC and lactose particles to a bi-continuous structure with a skeleton of porous cellulose with pores filled with the remaining formulation components. The soluble components can be removed from the pores by dissolution, leaving the porous MCC skeleton. The dependence of the microstructure on wet massing time, liquid level, and MCC content is reported.

Ammonio methacrylate copolymer as a carrier for water-insoluble drug, preparation and characterization of an oral controlled-release matrix tablet

The use of ammonia methacrylate copolymer as a carrier for the preparation of oral controlled-release matrix tablets containing water-insoluble drugs and investigating the effect of curing conditions. Tablets were cured at 40 °C with or without 75% relative humidity (RH). The crystalline structures were analyzed with powder X-ray diffractometry and dissolution studies were performed in USP dissolution apparatus type II. With increasing the ethanol content (0–20%, w/w) in the granulation fluid, the drug release was decreased. The drug release from the tablets cured at 70 °C/24 h was similar to those that cured at 40 °C with 75% RH/24 and the drug release kinetic was fitted with the zero-order release mechanism. The x-ray study showed no change in the crystalline structure of carbamazepine. As the curing duration, compression force and granule size were increased, the drug release was decreased. The drug release was proportionally changed with surface area/volume ratio, agitation rate, and polymer permeability; meanwhile, the release was unchanged with increased drug content from 30% to 50% w/w. Ammonio methacrylate copolymer could be used as a carrier for water-insoluble drugs and to prepare controlled-release matrix tablets.

Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation

Salt disproportionation (a conversion from the ionized to the neutral state) in solid formulations is a potential concern during manufacturing or storage of products containing a salt of the active pharmaceutical ingredient (API) due to the negative ramifications on product performance. However, it is challenging to find an effective approach to prevent or mitigate this undesirable reaction in formulations. Hence, the overall objective of this study is to explore novel formulation strategies to reduce the risk of salt disproportionation in pharmaceutical products. Crystals of pioglitazone hydrochloride salt were dispersed into polymeric matrices as a means of preventing the pharmaceutical salt from direct contact with problematic excipients. It was found that the level of salt disproportionation could be successfully reduced during storage or wet granulation by embedding a crystalline salt into a polymeric carrier. Furthermore, the impact of different polymers on the disproportionation process of a salt of a weakly basic API was investigated herein. Disproportionation of pioglitazone hydrochloride salt was found to be significantly affected by the physicochemical properties of different polymers including hygroscopicity and acidity of substituents. These findings provide an improved understanding of the role of polymeric carriers on the stability of a salt in solid formulations. Moreover, we also found that introducing acidifiers into granulation fluid can bring additional benefits to retard the disproportionation of pioglitazone HCl during the wet granulation process. These interesting discoveries offer new approaches to mitigate disproportionation of API salt during storage or processing, which allow pharmaceutical scientists to develop appropriate formulations with improved drug stability.

Design and Evaluation of Verapamil Hydrochloride Controlled Release Hydrogel-Based Matrix Tablets

Aim: The present work was aimed to formulate Verapamil hydrochloride (HCl) an antihypertensive agent as controlled release (CR) matrix tablets using naturally occurring hydrophobic gum such as dammar gum as a polymer. Methods: In the present investigation, an attempt was made to induce hydrogel formation using polyelectrolytes such as calcium hydroxide and sodium hydroxide with the dammar gum in the presence of dissolution media and to extend the drug release up to 12 h. The hydrogels thus formed could be able to diffuse the drug through the channels present in the hydrogel-based matrix tablets. CR hydrogel-based matrix tablets were prepared using various concentrations of dammar gum, calcium hydroxide, and sodium hydroxide by wet granulation technique using isopropyl alcohol as a granulating fluid. The prepared tablets were evaluated for pre- and post-compression parameters. In vitro dissolution studies were performed in 0.1 N HCl for the first 2 h and in 6.8 pH phosphate buffer for next 10 h. Results: Among various formulations, dammar gum with calcium hydroxide and sodium hydroxide in the concentrations of 1 mg and 2.5 mg, respectively, were showed extended drug release up to 12 h in a steady state manner. The swelling index, Fourier transform infra-red, differential scanning calorimetry studies and scanning electron microscopy analysis were also performed on both the optimized formulations indicated that there were no drug and excipient interactions, and these formulations were found to be stable.

Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40°C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration–dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution.