GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS (GMP)

CAPA Root Cause Analysis and Risk Management

CLEANING VALIDATION (Complete Theory)

Bioavailability and Bioequivalence Studies

PHARMA JOBS

STABILITY STUDY OF DRUG

NALINIKANTA SWAIN (FORMULATION RESEARCH SCIENTIST)

LIQUID DOSAGE FORM (SLIDE FORMAT)

NALINIKANTA SWAIN (FORMULATION RESEARCH SCIENTIST)

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NALINIKANTA SWAIN
FORMULATION RESEARCH SCIENTIST

www.nalinikantarnd.blogspot.com

Parenteral Preparations, Challenges in Formulations

Parenteral Preparations, Challenges in 

Formulations

Introduction

Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants. They are sterile preparations intended to be administrated directly into the systemic circulation in humans or animals.

They are required, like any pharmaceutical dosage form, to meet the pharmaceutical quality standards as described in pharma-copeias and to be safe for the intended purpose of use. In addition to being sterile, parenteral preparations must be pyrogen-free. Sterility can be achieved by different processes of sterilization that should be appropriate to the formulations, while the pyrogen-free aspect will require, if no depyrogenation process is used during the preparation of the sterile drug products, the use of pyrogen-free pharmaceutical ingredients; drug substances or API (Active Pharmaceutical Ingredient) and excipients.

They are usually supplied in single dose glass or plastic containers (PVC nowadays less recommended, or polyolefin) or more and more in pre-filled syringes or pens to facilitate the ease of use. This article will describe the main challenges encountered during the formulation of parenteral preparations, as well as Roquette’s solutions meeting the formulator’s needs.

Properties of Parenteral Preparations

Parenteral preparations are intended to be administrated through the human or animal body, either by direct injections (for example, bolus intravenous (IV), intramuscular (IM) or subcutaneous (SC)) or by infusion with a controlled infusion rate or by direct implantation through IM or SC. They must meet the following minimum com-pendia criteria:

• To be sterile and pyrogen-free
• To be clear or practically exempt of visible particle and to be free from sub-visible particles as required by pharmacopeias EP, USP and JP
• No evidence of phase separation for the emulsions, or aggregates formation for aqueous dispersions such as injectables Mab (monoclonal antibody) preparations
• In case of suspensions, the use of appropriate particle size and any sediment should be readily dispersed upon shaking to give stable formulations and ensure the correct dose to be withdrawn and injected.

Parenteral preparations may require the use of excipients that should be biocompatible, be selected for the appropriate use and to be included at the minimum efficient concentration. The functionality of these excipients is as follows:

• To make the preparations isotonic with respect to blood (glucose/dextrose, mannitol, sodium chloride…)
• To adjust the pH to the physiological one (mineral or organic acids or salts)
• To prevent the degradation of the drug substances (stabilizer…)
• To ensure or increase the drug substance’s solubility
• To provide adequate antimicrobial preservative property (only applicable to multidose preparations)

It should be stressed that excipients should not adversely affect the intended medicinal action of the drug products, nor at the concentration used to cause toxicity or undue local irritation.

  

   Challenges in        Formulations

 The main challenge of all   the different parenteral   dosage forms is to   achieve  a good   compatibility of the drug   substances with the excipients (no formation of new impurities either by degradation of the drug substance or formation of new chemical entity between the drug substance and the excipients) as well as the compatibility of the preparations with the primary container (no leachable or adsorption to container).

With regards to solutions and emulsions, the drug substances should be soluble and remain soluble during the entire shelf-life of the drug products. When drug substances are not soluble, dissolution can be achieved by the use of co-solvents, surfactants, or a soluble pro-drug, or eventually the use of solubility enhancers such as cyclodextrins thanks to the formation of inclusion complex.

The pH is one of the critical aspects of parenteral preparations which should have a pH close to the physiological one. However in certain cases, a compromise should be found between the pH ensuring stability of the drug substance (such for peptides requiring alkaline pH or proteins at pH close to the isoelectric point) and the physiological one. In all cases, large volume preparations (LVP, i.e. more than 100 ml as defined in pharmacopeia) should not contain a pH buffer as the blood has already a buffer effect property that could enter into competition with the injected drug product.

The stability of the drug substance is another critical point that a formulator can face during the development of the formulation. Unstable drug substances will lead to the formation of new impurities jeopardizing the safety of use of the preparations. When the use of a stabilizer is justified (for instance the use of mannitol as free-radical scavenger or cysteine in paracetamol solution for injection), it should be included at the minimum concentration demonstrated to be efficient at release and during the entire shelf-life.

In the cases of powders for injection or infusion obtained through a freeze-drying process, the use of bulking agent (such mannitol) and/or a cryoprotector will be needed when the dose of drug substance(s) cannot ensure solely the formation of acceptable “cake”.

Finally the process of the sterilization should be selected according to the characteristics of the parenteral preparations (for instance, heat steam sterilization for aqueous solutions and dry heat for non-aqueous solutions), but in any case it can be justified by the nature of the primary containers. Figures 1 and 2 display the decision trees for the selection of the sterilization process for aqueous products or non-aqueous solutions including semi-solid and dry powder products.

Figure 1. Decision tree for sterilization choices for aqueous products (CPMP/QWP/054/98)

Figure 2. Decision tree for sterilization choices for non-aqueous liquid, semi-solid or dry powder products (CPMP/QWP/054/98)

The efficiency of the selected sterilization process should be demon-strated through validation studies, using the appropriate biological indicators, to ensure an ASL (Assurance Sterility level) of 10-6.

Solutions

Roquette has developed a pyrogen-free range of products with high pharmaceutical standards and being biocompatible for the manufacture of parenteral preparations, All these pyrogenfree range of products are obtained from natural and renewable raw materials. Besides their compliance to pharmacopeias and other ICH quality requirements (for instance ICHQ3D for elemental impurities), all these pyrogen-free products, even when used as excipients, are manufactured in compliance to GMP, ICHQ7, and certified by competent authorities (ANSM the French Competent Authority and US FDA).

Conclusion

Parenteral preparations are sterile and pyrogen-free preparations intended to be administered directly into the systemic circulation in human or animal body. They should meet the pharmaceutical quality standards as described in pharmacopeias and ICH guidelines and also ensure the clinical tolerance as well as to be safe for the intended purpose of use.

NALINIKANTA SWAIN
FORMULATION RESEARCH SCIENTIST

www.nalinikantarnd.blogspot.com

Formulation and Evaluation of Antibacterial Creams and Gels Containing Metal Ions for Topical Application

Formulation and Evaluation of Antibacterial Creams and Gels Containing Metal Ions for Topical Application

Abstract

Background. Skin infections occur commonly and often present therapeutic challenges to practitioners due to the growing concerns regarding multidrug-resistant bacterial, viral, and fungal strains. The antimicrobial properties of zinc sulfate and copper sulfate are well known and have been investigated for many years. However, the synergistic activity between these two metal ions as antimicrobial ingredients has not been evaluated in topical formulations. Objective. The aims of the present study were to (1) formulate topical creams and gels containing zinc and copper alone or in combination and (2) evaluate the in vitro antibacterial activity of these metal ions in the formulations. Method. Formulation of the gels and creams was followed by evaluating their organoleptic characteristics, physicochemical properties, and in vitro antibacterial activity against Escherichia coli and Staphylococcus aureus. Results. Zinc sulfate and copper sulfate had a strong synergistic antibacterial activity in the creams and gels. The minimum effective concentration was found to be 3 w/w% for both active ingredients against the two tested microorganisms. Conclusions. This study evaluated and confirmed the synergistic in vitro antibacterial effect of copper sulfate and zinc sulfate in a cream and two gels.

1. Introduction

Topical skin infections commonly occur and often present therapeutic challenges to practitioners, despite the numerous existing antimicrobial agents available today. The necessity for developing new antimicrobial means has increased significantly due to growing concerns regarding multidrug-resistant bacterial, viral, and fungal strains [1–4]. Consequently, attention has been devoted to safe, new, and/or alternative antimicrobial materials in the field of antimicrobial chemotherapy.

Common examples for topical skin infections include diaper rash, cold sores, and tinea (also called pityriasis) versicolor. Diaper rash is a form of irritant contact dermatitis. It is one of the most common dermatological conditions encountered in babies while using diapers [5] and is estimated to occur in 7–35% of babies between the ages of 9 and 12 months [6]. Its development is multifactorial, including skin wetness, friction, skin irritants, and pH change, which favors the growth of microorganisms including Candida, Staphylococcus, and Streptococcus [7]. It has been shown that zinc and copper ions have antimicrobial activity against Staphylococcus aureus and Candida albicans [8]. Cold sores (also known as herpes labialis) are a common viral infection occurring on the lips, primarily caused by herpes simplex virus (HSV) type 1 [9]. Studies have shown that zinc and copper salts exhibit inactivation of HSV both in vivo and in vitro [10–13]. Zinc sulfate was found to have an antimicrobial effect in treating cold sores [14]. The molecular mechanism of its therapeutic effect was found to be the drastic inactivation of free virus in skin tissues, intercellular vesicles, and blisters [15]. Pityriasis versicolor is a superficial fungal infection of the skin, usually caused by Malassezia species. It is one of the most common skin diseases in tropical and subtropical areas and is characterized by fine scaly patches and macules [16]. Both zinc sulfate and copper sulfate have been found to be effective in treating this disease [17, 18].

In recent years, a number of metal ions have been studied as potential antimicrobial agents, including silver [19], copper [20], zinc [21], iron [22], magnesium [23], and titanium [24]. Zinc, alone or as an adjuvant, has been found to be advantageous in a number of dermatological infections and inflammatory diseases owing to its modulating actions on macrophage and neutrophil functions, natural killer cell/phagocytic activity, and various inflammatory cytokines. Zinc sulfate has been studied in vivo in a number of diseases, including warts [25], herpes genitalis [26], pityriasis versicolor [18], and acne vulgaris [27] in varying concentrations. Copper is well known for its antimicrobial properties. It has been used as an algicide, germicide, and fungicide for decades. Several antimicrobial mechanisms of copper were proposed in recent articles, including reactive hydroxyl radical formation leading to damaged cell integrity, denaturation of DNA by binding of copper to protein molecules, and inactivation of enzymes and obstruction of functional groups of proteins from displacement of essential ions [28–30]. Additionally, topically applied copper sulfate and hypericum perforatum were found to be efficacious in vivo in the treatment of herpes skin lesions [13].

The antimicrobial activity of zinc sulfate and copper sulfate has been investigated for many years. However, the synergistic activity between these two metal ions as antimicrobial ingredients has not been evaluated in topical formulations. The aim of the present study was to formulate topical creams and gels containing zinc sulfate or copper sulfate, and a combination of these, and to evaluate the in vitro antibacterial activity of these metal salts in the formulations against Escherichia coli and Staphylococcus aureus. The in vitro antibacterial activity of the formulated products was also compared to commercial products available for the treatment of diaper rash and cold sores.

Incorporating metal ions such as zinc and copper often creates a formulation challenge due to the high reactivity of these ions. Even trace amounts of metal ions are able to catalyze oxidation reactions in fatty compounds in products, leading to deterioration including odor formation, color change, and physical and/or chemical instability [31]. Metal ion reactions with the ingredients in the formulations can affect the quality, efficacy, consumer appeal, and shelf-life of formulations. Stability of product and of the antibacterial activity was studied for 12 weeks at two different temperatures in two different containers.

2. Materials and Methods

2.1. Materials

Copper sulfate pentahydrate was purchased from Fagron, Inc. (St. Paul, MN). Zinc sulfate heptahydrate, Carbomer 940, refined corn oil, almond oil sweet, lecithin soya granular, glycerin, and propylene glycol were purchased from Letco Medical (Decatur, AL). (ι)-Carrageenan was purchased from Sigma-Aldrich (St. Louis, MO). Hypromellose (Benecel, K4M PHARM, also known as hydroxypropylmethyl cellulose, HPMC), and Prolipid 141 (a mixture of glyceryl stearate, behenyl alcohol, palmitic acid, stearic acid, lecithin, lauryl alcohol, myristyl alcohol, and cetyl alcohol) were received as gifts from Ashland (Wilmington, DE). Kollidon® 90F (poly vinylpyrrolidone, PVP) was obtained from BASF (Ludwigshafen, Germany). Poloxamer 407 was purchased from PCCA (Houston, TX). FlexiThix™ (2-pyrrolidinone-1-ethenyl homopolymer) was received as a free sample from ISP Technologies, Inc. (Wayne, NJ). Xanthan gum, guar gum, methylparaben, propylparaben, butylated hydroxytoluene (BHT), and citric acid monohydrate were obtained from Spectrum Chemical (Gardena, CA). Medium chain triglycerides (MCT) were obtained from Mead Johnson & Company (Evansville, Indiana). Soybean oil, Cithrol™ GMS 40 (glyceryl stearate), Arlacel™ 165 (a mixture of glyceryl stearate and PEG-100 stearate), Tween 60, and Span 80 were received as free samples from Croda, Inc. (Edison, NJ). PEG-16 Macadamia and PEG-10 Sunflower were obtained from FloraTech (Gilbert, Arizona). Cocoa butter was a gift from Koster Keunen, Inc. (Watertown, CT). Cetyl alcohol, stearic acid, stearyl alcohol, and isopropyl myristate were obtained from Sherman Research Labs (Toledo, OH). Coconut oil was purchased from Spectrum Organic Products, (Melville, NY). Tefose HC (a mixture of cetyl alcohol, glyceryl stearate, ceteth-20, and steareth-20) was a free sample from Gattefossé (Saint-Priest Cedex, France). PEG-8 beeswax was a gift from Koster Keunen, Inc. (Watertown, CT). Urea was purchased from Gallipot®, Inc. (St. Paul, MN). Triethanolamine was purchased from Making Cosmetics (Snoqualmie, WA). Mueller-Hinton agar and gentamicin 10 μg standard discs were purchased from Becton, Dickinson and Company (Sparks, MD). The marketed products included Equate® Diaper Rash Relief Cream (distributed by Walmart, Inc.), Nexcare™ Cold Sore Treatment Cream (distributed by 3M), and Campho-Phenique® Cold Sore Treatment Gel (distributed by Bayer Health Care LLC), which were all purchased at a local Walmart store (Toledo, OH). All ingredients used in the various formulations can be found in Tables 1 and 2.

Table 1: Composition of the topical cream formulations.

Table 2: Composition of the topical gel formulations.

2.2. Methods

2.2.1. Formulation of the Topical Cream

The oil phase was prepared by melting the waxes at 75°C and mixing the ingredients uniformly. The aqueous phase was prepared by dissolving the water-soluble ingredients in deionized water. The water phase was warmed to 75–80°C until all ingredients were dissolved. When the water and oil phase were at the same temperature, the aqueous phase was slowly added to the oil phase with moderate agitation and was kept stirred until the temperature dropped to 40°C. The emulsion was cooled to room temperature to form a semisolid cream base. Zinc sulfate and copper sulfate were dissolved in warmed deionized water, and the solutions were added to the cream base using an overhead stirrer (Talboys Engineering Corp, Emerson, NJ). The mixture was stirred for 15 min until the formulation became uniform. The drug-loaded cream was preserved with paraben concentrate. The exact concentration of each ingredient is shown in Table 1.

2.2.2. Formulation of the Topical Gels

When using (ι)-carrageenan, xanthan gum, and guar gum, the powder polymers were dispersed in 75°C warm deionized water with stirring. When all the polymers were dissolved, the mixture was removed from the hot plate. The desired amount of zinc sulfate and copper sulfate was dissolved in the clear gel with intensive stirring. The mixture was then cooled to room temperature and preserved with paraben concentrate.

In formulations where HPMC was the thickening agent, the polymer was dispersed in 75°C warm deionized water with stirring. The resulting solution was stored at room temperature overnight until a clear gel formed. Zinc sulfate crystals and then copper sulfate crystals, after complete dissolution, were dispersed into the gel with intensive agitation. Preservative was added to the formulation in the last step.

Poloxamer was dissolved in cold water and stored under refrigerated conditions at 4°C for a night. The oil phase was prepared by mixing lecithin and isopropyl myristate in a 1 : 1 ratio. The mixture was stored at room temperature overnight for the complete dissolution of lecithin. The active ingredients were then added directly to the aqueous phase. The gel was prepared by mixing 1 part of oil phase with 4 parts of aqueous phase (poloxamer gel) using a vortex mixer (VORTEX-T, Genie® 2, Bohemia, NY).

Kollidon 90F, FlexiThix, and Carbomer 940 were directly dispersed into deionized water at room temperature with intensive agitation. Active ingredients were incorporated into the gel uniformly. In order for Carbomer 940 to form a gel, triethanolamine was added to neutralize the pH to 6–6.5. Table 2 shows the amount of ingredients used for the gels.

2.2.3. Physical Evaluation of the Topical Formulations

(1) Organoleptic Characteristics. All blank formulations (i.e., formulations without any active ingredients or preservatives) and drug-loaded formulations were tested for physical appearance, color, texture, phase separation, and homogeneity. These characteristics were evaluated by visual observation. Homogeneity and texture were tested by pressing a small quantity of the formulated cream and gels between the thumb and index finger. The consistency of the formulations and presence of coarse particles were used to evaluate the texture and homogeneity of the formulations. Immediate skin feel (including stiffness, grittiness, and greasiness) was also evaluated.

(2) Spreadability. Spreadability of the formulations was determined by measuring the spreading diameter of 1 g of sample between two horizontal glass plates (10 cm × 20 cm) after one minute. The standard weight applied to the upper plate was 25 g. Each formulation was tested three times.

(3) pH Values. One gram of each formulation (including the blank, i.e., formulation without any active ingredients or preservatives, and drug-loaded formulation) was dispersed in 25 mL of deionized water, and the pH was determined using a pH meter (Mettler-Toledo Ingold Inc., Billerica, MA). Measurements were made in triplicate. The pH meter was calibrated with standard buffer solutions (pH 4, 7, and 10) before each use.

(4) Viscosity Measurement. A Brookfield viscometer DV-I (Brookfield Engineering Laboratories, Middleboro, MA) was used with a concentric cylinder spindle #29 to determine the viscosity of the different topical formulations. The tests were carried out at 21°C. The spindle was rotated at 0, 0.5, 1, 2, 2.5, 4, 5, 10, 20, 50, and 100 rpm values. All measurements were made in triplicate.

2.2.4. In Vitro Antibacterial Activity

(1) Preparation of Mueller-Hinton (MH) Agar Plates. Mueller-Hinton (MH) agar medium was prepared according to the manufacturer’s instructions and autoclaved for 20 minutes at 20 psi. After autoclaving, the agar medium was cooled to 40–45°C in a water bath. Sixty mL of the cooled agar medium was poured onto the prepared  mm petri dish. The agar was allowed to cool to room temperature and stored in a refrigerator (2–8°C) until used.

(2) Preparation of Inoculum. Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 29213) were used to evaluate the antibacterial activity of the topical formulations containing zinc sulfate and copper sulfate. The microorganisms were subcultured the previous day to ensure that the tested microorganisms were in their log phase of growth and to ensure the validity of the results. One or two isolated colonies of the tested microorganisms were touched using a sterile cotton swab. The microorganisms were suspended in 2 mL of sterile saline medium and vortexed well until a uniform suspension was obtained. The turbidity of the suspension was measured at 625 nm using a UV-Vis spectrophotometer (Thermo Scientific, Waltham, MA). The turbidity of the suspension was adjusted to a 0.5 McFarland standard by adding more microorganism if the suspension was too light or diluting with sterile saline if the suspension was too heavy. The suspension was prepared before inoculating the microorganisms on the agar plate.

(3) Inoculation of the MH Plate. To inoculate the MH agar plates, a sterile cotton swab was dipped into the suspension and streaked over the surface of the agar plates. This procedure was repeated three times; each time, the plate was rotated approximately 60 degrees to ensure even distribution of the inoculum [32]. The plates were then allowed to dry at room temperature for 5 min before applying the drug.

(4) Preparation of Agar Well Diffusion Assay. The dried inoculated MH agar plates prepared above were used to perform the agar well diffusion assay. A sterile cork borer was used to make the wells by punching holes on the inoculated MH agar plates. Each well was 5 mm in diameter, and the cut-out of the agar was removed using a sterile needle. A desired amount of the formulations was weighed and placed into each well on an analytical balance. Gentamicin 10 μg standard discs were used as a control to ensure that the agar medium was appropriate to support the growth of the microorganism beyond the zone of inhibition. The gentamicin standard disc was placed and pressed gently onto the same inoculated agar plate by using sterile forceps. The inoculated agar plate was incubated at 37°C for 18 hours. The observed diameters of the zones of inhibition were measured by using a ruler to the nearest millimeter.

First, in order to observe how effective the active ingredients were alone versus combined, 20 μL of 3% copper sulfate, 3% zinc sulfate, 6% copper sulfate, 6% zinc sulfate, and % copper sulfate and zinc sulfate combined solutions were tested for antibacterial activity against E. coli and S. aureus. Next, the selected cream and gel formulations containing both active ingredients in a series of concentrations (including 0, 0.1, 0.25, 0.5, 1, 2, and 3% of each ingredient) were tested for antibacterial activity against E. coli and S. aureus to evaluate their effective concentration. Gentamicin 10 μg standard disc was used as the control. The sample size directly measured into the wells was  μg in this study. Finally, the selected cream and gel formulations were directly compared to the marketed products, including Nexcare Cold Sore Treatment Cream, Campho-Phenique Cold Sore Treatment Gel, and Equate Diaper Rash Relief Cream, in terms of their antibacterial activity against E. coli and S. aureus. The sample size directly measured into the wells was  μg in this study.

2.2.5. Stability Study

The antibacterial activity of all selected drug-loaded formulations was tested against E. coli using the above-described agar well diffusion assay for 12 weeks (measurements were made on day 1, week 3, week 6, week 9, and week 12). The antibacterial activity of the formulations was compared for samples stored at room temperature (25°C) and in the refrigerator (4°C) as well as those packaged into glass containers versus plastic containers. In addition to the antibacterial activity, pH values, color, physical appearance, and texture were also tested during the 12 weeks with the above-described methods.

2.2.6. Statistical Analysis

Statistical analysis of data was performed using one-way ANOVA (Tukey’s post hoc test). A difference was considered statistically significant when .

3. Results

From the twenty different creams formulated, C1 was selected as the final formulation for further testing. Eighteen different gels were formulated in this study, from which G1 and G5 were selected as optimal formulations for further evaluation.

3.1. Physical Evaluation of Topical Cream and Gels

3.1.1. Organoleptic Characteristics

The organoleptic properties, including physical appearance, color, texture, phase separation, homogeneity, and immediate skin feel of the selected topical formulations, are displayed in Table 3. Results showed that the cream and both gels had a cosmetically appealing appearance and smooth texture, and they were all homogenous with no signs of phase separation. All formulations were blue due to copper sulfate.

Table 3: Physicochemical evaluation of selected topical formulations.

3.1.2. Spreadability

Spreadability of semisolid formulations, that is, the ability of a cream or gel to evenly spread on the skin, plays an important role in the administration of a standard dose of a medicated formulation to the skin and the efficacy of a topical therapy. Figure 1 shows the spreading values, that is, diameters observed for the formulations, after one minute. The values refer to the extent to which the formulations readily spread on the application surface by applying a small amount of shear. Results indicated that our cream and gels had comparable spreadability to that of commercial products used as comparators in the study.

Figure 1: Spreadability values for the selected cream (C1) and gels (G1 and G5) compared to various marketed products (, results shown as mean ± SD).

3.1.3. pH Values

The pH values for the blank and drug-loaded cream and gels are shown in Table 4. The pH of the formulations decreased when the active ingredients were added to the bases. The pH of the skin normally ranges from 4 to 6. The pH of the cream was more acidic than that of the skin, while the gels’ pH values were similar to the skin’s normal pH value. The pH values of the formulations did not change significantly over the period of 12 weeks.

Table 4: pH of blank and drug-loaded formulations at day 1 and at week 12.

3.1.4. Viscosity Measurement

Viscosity values for the drug-loaded cream and gels are shown in Figure 2. All products had a pseudoplastic behavior, as expected. C1 and G1 had a similar viscosity curve, while G5 had a lower initial viscosity.

Figure 2: Viscosity curves for the selected cream (C1) and gels (G1 and G5) (, results shown as mean ± SD).

3.1.5. In Vitro Antibacterial Activity

The in vitro antibacterial study was performed by measuring and comparing the diameter of zones of inhibition (in mm) for the various products. The zone of inhibition can be defined as the clear region around the well that contains an antimicrobial agent. It is known that the larger the zone of inhibition, the more potent the antimicrobial agent.

In the first step, the two active ingredients’ antibacterial activity was measured individually and combined against E. coli and S. aureus. It can be concluded from the results that the antibacterial activity of zinc sulfate was higher than that of copper sulfate against the tested microorganisms (Figure 3). Results also confirmed that copper sulfate and zinc sulfate have a synergistic activity, as shown by their larger zone of inhibition against tested microorganisms ().

Figure 3: Antimicrobial activity of copper sulfate and zinc sulfate solutions in various concentrations against Escherichia coli and Staphylococcus aureus (, results shown as mean ± SD) ().

In the next step, the antibacterial activity of the selected cream (C1) and gels (G1 and G5) with varying amounts of active ingredients (0, 0.1, 0.25, 0.5, 1, 2, and 3%) was studied against E. coli and S. aureus. The results are shown in Table 5 and Figure 4. The blank formulation did not contain any active ingredients or any preservative. The formulation named paraben contained preservative but no active ingredients. Gentamicin 10 μg standard disc was used as the control in the study. No zone of inhibition was observed for the blank, paraben, and 0.1% strength formulations for either the cream or the gels. The zones of inhibition increased as the concentration of copper sulfate and zinc sulfate increased. This indicated that the antibacterial activity of copper sulfate and zinc sulfate increased against E. coli and S. aureus as the concentration of the actives was increased. As for the C1 formulation, the antibacterial activity of the sample containing 2% active ingredients was as good as that of the control (gentamicin) against S. aureus, while the antibacterial activity of the sample containing 3% active ingredients was statistically significantly higher than the control and the rest of the samples against both E. coli and S. aureus (). A visual representation of these results for C1 can be found in Figure 4. In the case of G1, similar results were seen. Samples containing 2% active ingredients had a similar antibacterial activity to that of the control, while the samples containing 3% active ingredients had statistically significantly higher activity against both microorganisms. As for G5, both the 2% and 3% samples had a similar antibacterial activity as the control against E. coli, while only the samples containing 3% of each active ingredient had an antibacterial activity comparable to the control against S. aureus. Based on the results, it can be concluded that both active ingredients have to be present in a concentration of at least 3% to achieve a similar or better antibacterial activity as the control against E. coli and S. aureus.

Table 5: Antimicrobial activity of the selected gel formulations in various dilutions against Escherichia coli and Staphylococcus aureus ().

Figure 4: Antimicrobial activity of the selected cream (C1) containing copper sulfate and zinc sulfate in various concentrations against (a) Escherichia coli and (b) Staphylococcus aureus (, results are shown as mean ± SD) ().

The final in vitro antimicrobial study was performed to compare the antibacterial activity of the selected formulations to those of marketed products against E. coli and S. aureus. As there is currently no marketed product available with zinc sulfate and copper sulfate, two commercially available cold sore gels and a diaper rash cream, Nexcare Cold Sore Treatment Cream, Campho-Phenique Cold Sore Treatment Gel, and Equate Diaper Rash Relief Cream, were used as comparators in the study. Nexcare Cold Sore Treatment Cream contains the following active ingredients: benzocaine as an external analgesic and allantoin as a skin protectant. The active ingredients in Campho-Phenique Cold Sore Treatment Gel are camphor and phenol as pain relievers or antiseptics, and, in Equate Diaper Rash Relief Cream, zinc oxide is a skin protectant. The results of this study are displayed in Figure 5. Results indicated that the antibacterial activity of C1, G1, and G5 was similar to that of the control (gentamicin), while the marketed products had a significantly lower activity against the two tested microorganisms. G1 and G5 had higher antibacterial activity against the tested bacteria than C1, which may be related to the composition of these products. The cream formulation contained oily components, which are immiscible with water and may slow down the diffusion of the drugs from the cream base.

Figure 5: Antimicrobial activity of the selected cream (C1), gels (G1 and G5), and three marketed products (Nexcare Cold Sore Treatment Cream, Campho-Phenique Cold Sore Treatment Gel, and Equate Diaper Rash Relief Cream) against Escherichia coli and Staphylococcus aureus (, results shown as mean ± SD).

3.2. Stability Study

All formulations maintained their blue color and intensity of color for 12 weeks in all storage conditions. Similarly, the physical appearance, homogeneity, and texture of all formulations remained the same by the end of the storage period. None of the formulations showed signs of physical or chemical instability in any of the containers or at any of the temperatures. The antibacterial activity of all formulations was maintained for 12 weeks in both containers and at both temperatures. Results are shown in Figure 6 for G5 as well as in Table 6 for C1 and G1.

Table 6: Antimicrobial activity during the stability study.

Figure 6: Antimicrobial activity of one of the selected gels (G5) during the stability testing compared to the control (gentamicin) against Escherichia coli (, results shown as mean ± SD).

4. Discussion

Twenty different cream bases (C1–C20) were formulated using different ingredients in varying concentrations. After incorporating the active ingredients into the bases, the physical stability of a number of bases was affected negatively by the metal ions, leading to creaming and breaking of the emulsions. Formulations C5–C20 suffered from such issues; therefore, they were discontinued from further characterization. Formulations C1–C4 were formulated with the same ingredients, but with varied concentrations of the emulsifiers and thickeners. These four creams had similar consistency, and no apparent change in their physical appearance was observed after adding the metal salts. Based on the overall evaluation for physical appearance and immediate skin feel, C1 was selected as the final formulation for further testing.

In addition to the creams, eighteen different gels (G1–G18) were formulated using eight different gelling agents. Only two polymers, namely, carrageenan and HPMC, proved to be optimal gelling agents for the metallic active ingredients used. G1 and G2 were formulated using carrageenan. These gels incorporated the active ingredients well. They had similar texture, consistency, and viscosity. The appearance, viscosity, and skin feel provided by G1 was considered better for a topical gel; therefore, it was selected for further testing. G3–G6 were formulated using different concentrations of HPMC. Out of these four samples, only G5 provided an optimal gel. To be considered optimal in this study, a gel (1) had to be homogenous without showing signs of physical or chemical instability; (2) had to be able to dissolve and keep the active ingredients in a dissolved form without precipitating or aggregating; and (3) had to have a high enough viscosity not to flow off the skin during/after application. In the case of G3 and G4, precipitation or aggregation of the polymers was observed when the active ingredients were added to the 5% HPMC gel. The explanation for this is that the amount of water used in these gels was not enough to dissolve the crystalline actives and keep the gelling agent dispersed. G4 contained more water compared to G3; however, even that higher amount did not prove to be enough for a stable formulation. G5 met all our requirements; therefore this formulation was selected for further testing. G6 had a too low viscosity, which was not deemed appropriate for a topical gel. As for the other polymers used, including xanthan gum, guar gum, poloxamer 407, Kollidon 90F, FlexiThix, and Carbomer 940, the gels’ physical stability was compromised when the active ingredients were added to the gel bases.

The three selected formulations were optimal in terms of their appearance, homogeneity, and viscosity. Previous studies [6–9] indicated that both active ingredients had antibacterial activity, which this study confirmed. The two metal salts had a synergistic activity when combined in the creams and gels, which was also confirmed by our study. The second antibacterial study indicated that both zinc sulfate and copper sulfate have to be present in at least a 3% concentration in order to achieve similar or better results against the tested microorganisms than gentamicin, which was used as the control. As there are no marketed products available today with copper sulfate and/or zinc sulfate, commercial products for the treatment/prevention of cold sores and diaper rash with active ingredients other than copper sulfate and zinc sulfate were used as comparators in the final antibacterial study. This limited study showed that the formulated creams and gels had a significantly higher antibacterial activity against the two tested microorganisms than the marketed products. With a properly planned and conducted follow-up study using additional microorganisms—preferably fungi, bacteria, and viruses—the true antimicrobial activity of the products could be evaluated, and a more realistic comparison could be made.

The stability study indicated that both gels and the cream were able to maintain their integrity for 12 weeks without showing signs of instability. Additionally, the main function, that is, antibacterial activity of all formulations, remained stable for the tested time period, which is promising. As discussed in the introduction, incorporating metal salts into emulsions and gels can be a challenging task for formulators due to the high reactivity of these salts. Many of our formulations were affected by the metal ions, which resulted in precipitation, phase separation, color change, and other forms of instability. Only a few formulations, that is, the selected creams and gels, were able to remain stable after incorporating the active ingredients into them.

5. Conclusions

In this study, various creams and gels were formulated with copper sulfate and zinc sulfate, which act as antimicrobial agents. During the formulation process, the quality, appearance, and stability of many creams and gels were affected by the highly reactive metal ions. A cream and two gels were found to be optimal for our purpose, and these were selected for further evaluation based on their physical properties, in vitro antibacterial activity, and product stability. Although only a small fraction of the formulated products were deemed optimal, a great achievement is that the integrity, pH values, texture, appearance, and antibacterial activity of these selected products were maintained for 12 weeks.

A major finding of this study is that copper sulfate and zinc sulfate have a synergistic antibacterial activity in creams and gels. The minimum effective concentration in vitro was found to be 3% for both active ingredients. A properly planned and conducted in vitro follow-up study could confirm the antimicrobial activity of the formulations against other microorganisms, and a more realistic comparison could be made between our products and marketed products for various skin conditions.

NALINIKANTA SWAIN

FORMULATION RESEARCH SCIENTIST

www.nalinikantarnd.blogspot.com

       Solid Dosage Forms: Tablets

Tablets are solid dose pharmaceutical preparation containing drug substances usually prepared with the aid of suitable pharmaceutical excipients. They may vary in size, shape, weight, hardness, thickness, disintegration and dissolution characteristics and in other aspects, depending on their intended use and method of manufacture.

Tablets constitute approximately 90% of all dosage forms clinically used to provide systemic administration of therapeutic agents. This widespread use of tablets has been achieved as a result of their convenience and also the diversity of tablet types.

Tablets are prepared primarily by compression of granules or powder blends, with a limited number prepared by moulding. Most tablets are used in the oral administration of drugs. Many of these are prepared with colourants and coatings of various types. Other tablets, such as sublingual, buccal, or vaginal tablets, are prepared to have features most applicable to their particular route of administration.

General Properties of Tablets

• A tablet must be strong and hard to withstand mechanical shock during manufacturing, packing, shipping, dispensing and use.
• The drug content of the tablet must be bioavailable that is, the tablet must be able to release its content in a predictable and reproducible manner.
• The tablet must be chemically and physically stable to maintain its chemical and physical attributes during manufacture, storage, and use.
• The tablet should have elegant product identity which is free from any tablet defect.
• Tablets must be uniform in weight and in drug content.

Types of tablets

The various tablet types are described as follows:

a. Compressed tablets

Compressed tablets represent a significant proportion of tablets that are clinically used to provide systemic administration of therapeutic agents either in an uncoated state (i.e., in their simplest form) or in a coated state. These tablets are designed to provide rapid disintegration in the gastric fluid following ingestion hence, allowing rapid release of the drug and, ultimately, systemic absorption of the dosage form.

Compressed tablets are formed by compression of powdered, crystalline, or granular materials into the required geometry by the application of high pressures, utilizing steel punches and die. In addition to the Active Pharmaceutical Ingredient(s) (APIs), compressed tablets usually contain a number of pharmaceutical excipients e.g., bulking agents, disintegrants, binders, lubricants, controlled-release polymers and other miscellaneous adjuncts such as colourants and flavourants which serve different and specialized purpose during tablet manufacture, storage, and use. Examples of compressed tablets include tablets for oral, buccal, sublingual, or vaginal administration.

b. Sugar-coated Tablets

These are compressed tablets that have been coated with concentrated sugar solution to improve patient’s compliance, increase aesthetic appeal, mask objectionable tastes or odours, increase stability and/or modify the release of therapeutic agent(s). Sugarcoating was once quite common but lost commercial appeal due to the time and expertise required in the coating process, the increase in size and weight of coated tablets, high cost of process validation and shipping.

The advent of film-coated tablets has also greatly decreased the use of sugar coatings due to the improved mechanical properties of the technique. Examples of sugar-coated tablets include Reasulf tablets – dried ferrous sulphate BP 200mg (Reagan Remedies Ltd.), Advil – Ibuprofen tablet BP 200mg (Pfizer Consumer Healthcare), Ebu-200 – Ibuprofen tablet BP 200mg (Me cure Industries Ltd) etc.

c. Film-Coated Tablets

Film-coated tablets are conventional tablets coated with a thin layer of polymer (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose) or a mixture of polymers (e.g., Eudragit E100) capable of forming a skin-like film. The film is usually coloured and also impacts the same general characteristics as sugar coating with the added advantage of being more durable, less bulky, and less time-consuming to apply. By its composition, the coating is designed to break and expose the core tablet at the desired location in the gastrointestinal tract.

Advances in material science and polymer chemistry have made these coatings the first choice for formulation scientists. Examples of Film-coated tablets include Curefenac 100 – Diclofenac potassium USP 100mg (Unicure Pharmaceutical Ltd), Valsartan 320mg Film-coated Tablets (Actavis UK Ltd), etc.

d. Effervescent Tablets

Effervescent tablets are uncoated tablets that generally contain organic acids (such as tartaric or citric acid) and sodium bicarbonate in addition to the medicinal substance or API.  They react rapidly in the presence of water by releasing carbon dioxide which acts as a disintegrator to produce either a drug suspension or an aqueous solution. These tablets are prepared by compressing granular effervescent salts (organic acid and bicarbonate) with the medicinal substances. A typical example of this tablet type is Ca C1000 Sandoz effervescent tablet (Novartis).

e. Enteric-coated Tablets

Enteric-coated tablets are compressed tablets that have delayed-release properties. They are coated with polymeric substances (such as cellulose acetate phthalate/cellulose acetate butyrate; hydroxypropylmethylcellulose succinate; and methacrylic acid copolymers) that resist solution in gastric fluid but disintegrate and allow drug dissolution and absorption in the intestine.

Enteric coatings are primarily employed when the drug substance is inactivated or destroyed by gastric acid (e.g., erythromycin) or is particularly irritating to the gastric mucosa (e.g., non-steroidal anti-inflammatory drugs) or when bypass of the stomach substantially enhances drug absorption. Example of enteric-coated tablets includes Lofnac 100 – Diclofenac sodium delayed-release tablet USP 100mg (bliss GVS Pharma Ltd), Ecotrin tablets and caplets (GlaxoSmithKline Beecham).

f. Chewable Tablets

Chewable tablets are big sized tablets which are difficult to swallow and thus, are chewed within the buccal cavity prior to swallowing. They are especially useful for administration of large tablets to children and adults who have difficulty swallowing conventional tablets or antacid formulations in which the size of the tablet is normally large and the neutralisation efficacy of the tablet is related to particle size within the stomach.

Chewable tablets are not conventionally used if the drug has issues regarding taste acceptability. Examples of chewable tablets include Danacid – compound magnesium trisilicate tablet B.P. (Dana Pharmaceuticals Limited), Gestid – tasty chewable antacid (Ranbaxy) etc.

g. Buccal and Sublingual Tablets

Buccal and sublingual tablets are small, flat, oval tablets that are intended to be dissolved in the buccal pouch (buccal tablets) or beneath the tongue (sublingual tablets) for absorption through the oral mucosa to produce a systemic effect. These tablets are employed to achieve either rapid absorption into the systemic circulation e.g. glyceryl trinitrate sublingual tablets or, alternatively, to enable oral absorption of drugs that are destroyed by the gastric juice and/or are poorly absorbed from the gastrointestinal tract.

h. Lozenges or Troches

These are disc-shaped solid preparations containing medicinal agents and generally a flavouring substance in a hard candy or sugar base. They are intended to be slowly dissolved in the oral cavity, usually for local effects.

Examples include Strepsils Dry Cough Lozenges – Dextromethorphan Hydrobromide 5mg, Dichlorobenzyl alcohol 1.2mg, Amylmetacresol 0.6mg (Reckitt Benckiser), Dequadine – Dequalinium chloride BP 250mcg (Evans Medical PLC), Dr Meyer Coflin cough lozenges (Meyer Organics PVT Ltd), Cofta – Ammonium chloride/ Ipecacuanha tablet (Evans Medical PLC) etc.

i. Tablet Triturates

Tablet triturates are small, usually cylindrical, moulded, or compressed tablets containing small amounts of usually potent drugs mixed with a combination of sucrose and lactose or any suitable diluent. They are prepared from moist material, using a triturate mould that gives them the shape of cut sections of a cylinder.

Since tablet triturates must completely and rapidly dissolve in water, only a minimal amount of pressure is applied during their manufacture. One of the problems encountered during the manufacture of this tablet type is the failure to find a lubricant that is completely water-soluble. A typical example of tablet triturate is NTG tablets.

j. Hypodermic Tablets

Hypodermic tablets are soft, readily soluble tablets that were originally used by physicians in extemporaneous preparation of parenteral solutions. These tablets are dissolved in a suitable vehicle (water for injections) and administered by parenteral route.

Hypodermic tablets are no longer used in most countries due to the difficulty in achieving sterility. Also, the availability of stable parenteral solutions and prefabricated injectable products, some in disposable syringes have also discouraged their use in recent times. e.g., Dilaudid – Dihydromorphinone HCl (Bilhuber Knoll Corp.).

k. Dispensing Tablets

Dispensing tablets also referred to as compounding tablets are tablets supplied primarily as a convenience for extemporaneous compounding. These tablets contain large amounts of highly potent APIs, and thus are used by a pharmacist to compound prescriptions that can be incorporated readily into powders and liquids, thus, circumventing the necessity to weigh small quantities of these potent drug substances.

Dispensing tablets are no longer in use and had the dangerous potential of being inadvertently dispensed as such to patients. Examples include silver potentiate, bichloride of mercury merbromin and quaternary ammonium compounds.

l. Gelatin-Coated Tablets

Gelatin-coated tablets are compressed tablets coated with either one or two-toned colour gelatin. The gelatin coating impacts the same general characteristics as sugar coating and film coating with the added advantage of improving the stability of photosensitive APIs.

The gelatin coating also facilitates swallowing, enables custom branding,  and prevents counterfeit since they are more tamper-evident than unsealed capsules. Gelatin-coated tablets are also ideal for double-blind clinical studies, or for drug substances that can irritate the oesophagal mucosa when they are incorporated in an immediate-release tablet such as bisphosphonates.

Example of gelatin-coated tablets includes gelatin-coated hydrochlorothiazide tablet (Qualitest Pharmaceuticals), Tylenol Cold Multi-Symptom Daytime (McNeil Consumer) etc.

m. Multiple Compressed Tablets/ Multi-compressed Tablets

Multiple compressed tablets, also called multi-compressed tablets are tablets that are composed of two or more layers. These tablets are prepared by subjecting the fill material to more than one compression cycle.

The result may be a multiple-layer tablet or a tablet within a tablet, the inner tablet being the core and the outer portion being the shell. This process is best used when separation of active ingredients is needed for stability purposes or if the mixing process is inadequate to guarantee uniform distribution of two or more active pharmaceutical ingredients.

Multiple compressed tablets can also be used when there is a need to mask the bitter taste of a drug substance or where the drug substance in question is irritant to the stomach. There are three subclasses of multiple compressed tablets and they include compression coated tablets, layered tablets and inlay tablets.

i. Compression Coated Tablets

Compression coated tablets also referred to as dry-coated tablets or press-coated tablets, are tablets with two parts; internal core and surrounding coat. These tablets are prepared by feeding previously compressed tablets into a special tablet press (e.g., Manesty Drycota) and compressing another granulation layer around a preformed tablet core.

Compression coated tablets have all the advantages of compressed tablets (i.e., slotting, monogramming, speed of disintegration) while retaining the attributes of sugarcoated tablets in masking the taste of the drug substance in the core tablets.

These tablets can also be used to separate incompatible drug substances (one in the core and the other in the coat); in addition, they can provide a means of giving an enteric coating to the core tablets.

ii. Layered Tablets

They are tablets composed of two or more layers of ingredients. Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation to form two-layered or three-layered tablets, depending on the number of separate fills. Each layer may contain a different medicinal agent, separated for reasons of physical or chemical incompatibility, staged drug release, or simply the unique appearance of the layered tablet.

Unlike conventional tablets where we have a single piece of substance moulded to shape, layered tablets have the appearance of a sandwich because the edges of each layer are exposed.

iii. Inlay Tablets

Inlay tablets, popularly known as dot, or bull’s-eye tablets are variation of compressed tablets with a partially surrounded core. Instead of the tablet core being completely surrounded by the coating, its top surface is completely exposed.

Inlay tablets are prepared by feeding previously compressed tablets into a prefilled die cavity of Stokes, Colton, or Kilian machines. When compressed, some of the coating material is displaced to form the sides.  With a yellow core and a white coating, Inlay tablets resemble a fried egg.

Inlay tablets can be useful in sustained-release preparations to reduce the size and weight of the tablet. A typical example is a European preparation containing 25 mg of hydrochlorothiazide in the bull’s-eye and 600 mg of potassium chloride in the outside portion.

n. Immediate-Release Tablets

Immediate-release tablets are tablets designed to disintegrate and release their medication with no special rate-controlling features, such as special coatings and other techniques. This is the most common type of tablet and examples include, chewable, effervescent, sublingual and buccal tablets.

o. Rapid-release Tablets

Rapid-release tablets, also called rapidly dissolving tablets, rapidly disintegrating tablets, orally-dispersible tablets, quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast-dissolving tablets, rapid-dissolving tablets, or porous tablets are characterized by disintegrating or dissolving in the mouth within 1 minute, some within 10 seconds, leaving an easy-to-swallow residue.

Tablets of this type are prepared using very water-soluble excipients designed to wick water into the tablet for rapid disintegration or dissolution without chewing.

Rapid-release tablets offer increased convenience and ease of administration with the potential to improve compliance, especially when swallowing conventional solid oral-dosage forms presents difficulties for the patient.

Notwithstanding these advantages, there are a number of disadvantages and difficulties associated with formulating rapid-release tablets, including drug loading, taste masking, friability, manufacturing costs, and stability of the product.

Examples of rapid-release tablets include Clarinex Reditabs [desloratadine], Schering.

p. Extended-Release Tablets

Extended-release tablets sometimes called controlled-release tablets, prolonged-release, delayed release or sustained release tablets are tablets designed to release their medication in a predetermined manner over a prolonged period of time. These tablet types are categorized into

• Those that respond to some physiological condition to release the drug, such as enteric coatings;
• Those that release the drug in a relatively steady, controlled manner; and
• Those that combine combinations of mechanisms to release pulses of drug such as repeat action tablets.

A typical example of this tablet type is Divalproex-Sodium-Extended-Release-Tablets.

q. Vaginal Tablets/ Vaginal Inserts

Vaginal tablets are uncoated, bullet-shaped, or ovoid tablets designed for vaginal administration. They are prepared by compression and are shaped to fit tightly on plastic inserter devices that accompany the product.

Following insertion, retention and slow dissolution of the tablet occur, releasing the medicaments to provide the local pharmacological effect (e.g. for the treatment of bacterial or fungal infection).

Vaginal tablets may also be used to provide systemic absorption of therapeutic agents. Examples include Gyno-Tiocosid (Neimeth), Gynesatum- Clotrimazole vaginal Tablet (Chazmax Pharmaceutical Industries Limited), Nystamark-Nystatin Vaginal Tablet (Mark Pharmaceuticals) etc.

r. Implantation Tablets/ Implants

These are long-acting sterile tablets designed to provide continuous release of drugs, often over a period of months or a year. They are placed subcutaneously for systemic or local delivery.

Implants are mainly used for the administration of hormones such as testosterone steroids for contraception. They usually contain rate-controlling excipients in addition to the active ingredient(s).

Several types of implants are available including pellets, resorbable microparticles, polymer implants, in situ–forming gel/solid implants, metal/plastic implants, and drug-eluting stents.

Examples of implantation tablets include Implanon – etonogestrel (Organon), Disulfiram Tablet for Implantation etc.

Tablet Excipients/ Ingredients

In tablet formulation, many materials are usually combined at various quantities to produce a tablet that is of good standard. These materials serve different and specialized functions in the tablet. The type and quantity of each raw material used is dependent on the intended tablet type and formulation technique. Tablet Excipients include:

• Binders /granulating fluid –e.g., include acacia gum, tragacanth, corn starch, methylcellulose, gelatin, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and sugars, such as sucrose, glucose, dextrose, molasses, and lactose etc.
• Bulking agents/ diluents/fillers –e. g., anhydrous lactose, spray dry lactose, microcrystalline cellulose, corn starch, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, etc.
• Disintegrating agents – e.g., starch, clays, celluloses, algins, gums, and cross-linked polymers (croscarmellose, crospovidone, and sodium starch glycolate) etc.
• Lubricants –e. g., metallic stearate (0.1-0.2 % w/w) e.g., magnesium stearate, calcium stearate, stearic acid (0.25-1 %), hydrogenated vegetable oil, corn starch, boric acids, sodium chloride, sodium lauryl sulphate etc.
• Glidants – e.g., colloidal silicon dioxide Cab-o-sil (Cabot), Talc (asbestos-free) etc.
• Colouring agents/ Colourants – e.g., FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, D&C Green No. 5, D&C Red No. 6, D&C Red No. 21. D&C Red No. 22, D&C Red No. 27 etc.
• Flavoring agents/ Flavorants – e.g., Aspartame (Pfzer)
• Adsorbent – e.g., silicon dioxide, magnesium oxide, starch, magnesium silicate etc.

How Tablets are Manufactured

Tablets are commonly manufactured by one of the following manufacturing processes:

Wet granulation

1. Milling of drugs and excipients.
2. Mixing of drugs and excipients (excluding the lubricant).
3. Preparation of binder dispersion.
4. Mixing of binder solution with powder to form a coarse mass.
5. Coarse sieving
6. Drying of moist granules.
7. Sieving of the dried granules and mixing with disintegrant and lubricant.
8. Compression into tablets.

Dry granulation (slugging or roller compaction/ chilsonisation)

1. Milling of drugs and excipients.
2. Mixing of milled powders.
3. Compression of mixed powders into slugs (big tablets).
4. Milling and sieving of the slugs.
5. Mixing with disintegrant and lubricant.
6. Compression into tablets

Direct compression

1. Milling of drugs and excipients.
2. Mixing of powders, disintegrant and lubricant.
3. Compression into tablet

Advantages of Tablets in the Pharmaceutical industry

• Tablets are elegant in appearance and convenient to use.
• They are superior to other dosage forms with respect to chemical, physical and microbiological stability.
• Tablets provide stable and an accurately measured dosage of drug substance to patients.
• Tablets can be formulated to protect unstable drug substances or disguise unpalatable excipients.
• Tablets are generally inexpensive to manufacture.
• It is easier to mask the unpleasant taste of some APIs in tablets thus improving patient acceptability.
• Tablets may be formulated to contain two or more drug substances (even if they are physically or chemically incompatible), thus reducing multiple tablet use.
• Tablets may be easily manufactured to show product identification using coloured coatings, embossed markings, and printing.
• Tablets may be designed to release their active substance at a particular site within the gastrointestinal tract to reduce side effects, promote absorption at that site or provide a local effect (e.g. ulcerative colitis).
• With the exception of proteins which are denatured in the gastrointestinal tract, all classes of therapeutic agents may be administered orally in the form of tablets

Disadvantages of Tablets

• The manufacture of tablets requires a series of unit operations (weighing, milling, drying, mixing etc.) thus there is an increased level of product loss at each stage in the formulation process.
• The absorption of medicament from tablets is dependent on physiological factors, such as gastric resident/emptying time, and thus, vary from one .patient to another.
• The compression properties of certain drug substance are poor and may present problems in their subsequent formulation and manufacture as tablets.

Conclusion

Tablets remain popular as a dosage form, due to the various advantages afforded both to the manufacturer and to the patient. Although the basic mechanical approach for most tablet manufacture has remained the same, efforts are continuously made to understand more clearly the physical characteristics of powder compaction and the factors affecting the availability of the drug substance from the dosage form after oral administration.

NALINIKANTA SWAIN

FORMULATION RESEARCH SCIENTIST

www.nalinikantarnd.blogspot.com