Pharmaceutical Solid Dosage Forms Research Articles

A Review: Novel Granulation Technology

All the pharmaceutical Active pharmaceutical Ingredients (API) and Pharmaceutical excipients will have different particle size. While formulating a dosage form, particles from raw materials will tend to separate from other due to their rheological properties. There could be a condition where fine particles separate from the larger particles causing demixing or uneven distribution of active with its excipients leading to tablet content uniformity issue. To overcome this problem, particle enlargement or particle cohesiveness with or without additional aid is necessary, which could be achieved by granulation. Hence granulation technology is important in the formulation of pharmaceutical oral solid dosage form. Granulation is the process of adhering fine particles agglomerate into a large particle using two most common methods i.e. wet granulation and dry granulation/compaction. Day by day technological innovation is happening in all fields and pharmaceutical granulation process is also not an exemption. The objective of present review is to focus the novel granulation technology and how it is differing from the conventional granulation technology.

Tableting behavior of freeze and spray-dried excipients in pharmaceutical formulations

Most of biopharmaceuticals, in their liquid form, are prone to instabilities during storage. In order to improve their stability, lyophilization is the most commonly used drying technique in the pharmaceutical industry. In addition, certain applications of biopharmaceutical products can be considered by oral administration and tablets are the most frequent solid pharmaceutical dosage form used for oral route. Thus, the tableting properties of freeze-dried products used as cryo and lyoprotectant could be a key element for future pharmaceutical developments and applications. In this study, we investigated the properties that might play a particular role in the specific compaction behavior of freeze-dried excipients. The tableting properties of freeze-dried trehalose, lactose and mannitol were investigated and compared to other forms of these excipients (spray-dried, commercial crystalline and commercial crystalline milled powders). The obtained results showed a specific behavior in terms of compressibility, tabletability and brittleness for the amorphous powders obtained after freeze-drying. The comparison with the other powders showed that this specific tableting behavior is linked to both the specific texture and the physical state (amorphization) of these freeze-dried powders.

Separation and quantification of organic‐related impurities of beta‐adrenergic receptor blocking agent propranolol in pharmaceutical solid dosage forms: Impurity profiling using stability‐indicating HPLC method

AbstractPropranolol hydrochloride (PPH) is a medication of beta‐adrenergic receptors. It is used to treat pediatric hemangiomas that are growing and need systemic therapy. A reversed‐phase high‐performance liquid chromatography (HPLC) was made to separate and estimate the amounts of ten known organic impurities of propranolol in bulk drugs, tablets, and capsule dosage forms. The chromatographic separation was achieved on a C18 column (100 × 4.6 mm, 2.7 μm) using a binary gradient mixture of pH 2.3 phosphate buffer and organic modifiers of acetonitrile, methanol, and isopropyl alcohol as the mobile phase. The stability‐indicating character of the proposed method was proven using stress testing study. The test method was validated for specificity, limit of detection, limit of quantitation, linearity, precision, accuracy, and robustness. For the propranolol and its ten organic impurities, the limit of quantitation, linearity, and recoveries were found in a range of 0.0123–0.4266 μg/mL (R2 > 0.9982) and 89.2–98.9%, respectively. The proposed liquid chromatography method is found to be highly suitable for impurity profiling of propranolol in bulk drugs and pharmaceutical formulations (tablets and capsules).

Tableting properties of freeze-dried trehalose: Physico-chemical and mechanical investigation

Freeze-drying of biopharmaceutical products is the method of choice in order to improve their stability and storage conditions. Such freeze-dried products are usually intended for parenteral route administration. However, many biopharmaceutical materials administered by parenteral route are used to treat local diseases particularly in the gastro-intestinal tract. Therefore, many studies concentrate nowadays their effort on developing alternative dosage forms to deliver biopharmaceutical molecules by the oral route. Tablets are the most popular solid pharmaceutical dosage form used for oral administration since they present many advantages, but poor informations are available on the possibility of tableting freeze-dried powders. In this study, we evaluate the compaction behavior of freeze-dried trehalose powder since trehalose is one of the most used cryo and lyoprotectant for the lyophilisation of biopharmaceutical entities. Results show that freeze-dried trehalose powder can be tableted while remaining amorphous and the obtained compacts present very specific properties in terms of compressibility, tabletability, brittleness and viscoelasticity compared to the crystalline trehalose and compared to classical pharmaceutical excipients.

A Novel, Economical RP-HPLC Method for Quantification of Cefixime in Bulk and Pharmaceutical Solid Dosage form

A new, precise, economical, and linear gradient reverse phase high-performance liquid chromatography (RP-HPLC) method has been developed and validated for assay determination in Cefixime. The chromatographic separation was achieved with Hypersil C18(250*4.6)mmand 3 µm particle size column. The flow rate was 1.0 mL/min and eluents were detected at 220 nm using PDA detector. The retention time was found to be 7.3 min.The percentage recoveries for molecules were found to be in the range of 99–101%. The calibration curve demonstrated good linearity in the range of 20–100 gm/ml. for Cefixime. The approach has been validated in accordance with the International Conference on Harmonization's regulatory criteria. The evaluated parameters are precision, linearity, detection limit, quantification limit, specificity, accuracy, and robustness.The technique may be applied to stability investigations as well as routine analysis to identify and quantify Cefixime in pharmaceutical dosage form .
 Keywords: Cefixim. Reversed Phase High Performance Liquid Chromatography. Assay substances. Methanol

Machine learning framework for extracting micro-viscoelastic and micro-structural properties of compressed oral solid dosage forms

A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product’s Critical Quality Attributes, such as disintegration, drug release (dissolution) profile, and structural strength (“hardness”), are influenced by its micro-scale properties. Ultrasonic evaluation is direct, non-destructive, rapid, and cost-effective. However, for practical process control applications, the simultaneous extraction of the micro-viscoelastic and scattering properties from a tablet’s ultrasonic response requires a unique solution to a challenging inverse mathematical wave propagation problem. While the spatial progression of a pulse traveling in a composite medium with known micro-scale properties is a straightforward computational task when its dispersion relation is known, extracting such properties from the experimentally acquired waveforms is often non-trivial. In this work, a novel Machine Learning (ML)-based micro-property extraction technique directly from waveforms, based on Multi-Output Regression models and Neural Networks, is introduced and demonstrated. Synthetic waveforms with a given set of micro-properties of virtual tablets are computationally generated to train, validate, and test the developed ML models for their effectiveness in the inverse problem of recovering specified micro-scale properties. The effectiveness of these ML models is then tested and demonstrated for a set of physical OSD tablets. The micro-viscoelastic and micro-structural properties of physical tablets with known properties have been extracted through experimentally acquired waveforms to exhibit their consistency with the generated ML-based attenuation results.

Energy efficient smart manufacturing of pharmaceutical solid oral dosage forms

Background: The global pharmaceuticals market is a trillion-dollar industry which grows more than 5% annually. However, in comparison to other manufacturing industries (e.g., oil refining, automotive), the pharmaceutical sector lags in manufacturing innovation and automation. In the production of pharmaceutical solid dosage forms, the use of energy utilization as a performance measure of production efficiency has neither been implemented extensively, nor been optimized to maximize efficiency. This study will focus on the development and implementation of a smart manufacturing platform to optimize energy productivity whilst maintaining tablet quality via the consideration of different manufacturing scenarios.
 Methods: This study will consider three main unit operations (wet granulation, drying and milling) which are relatively more energy intensive in pharmaceutical downstream processing, used to produce solid dosage forms, such as tablets. Four case-studies will be considered, which are 1: baseline batch, 2: baseline continuous, 3: optimized batch and 4: optimized continuous. Smart manufacturing is implemented to present optimized cases 3: and 4: Improvements in the energy and performance metrics are quantified and compared to the baseline cases. 
 Results and conclusions: The smart manufacturing platform used in this study, integrates advanced process model development, optimization, technoeconomic analysis and data integration. The utilization of this framework contributed to a ~70% and ~80% improvement in energy utilization in the optimized batch and continuous cases, respectively, when compared to the baseline batch case. In the optimized cases, tablet quality was maintained within targeted specifications and was comparable to the baseline batch case. This smart manufacturing framework can be generalized for drug product manufacturing and other particulate-based industries such as food, agriculture, and fine chemicals.

Carboxymethyl Starch Films as Enteric Coatings: Processing and Mechanistic Insights

This study proposes the application of carboxymethyl starch derivatives as tablet coatings affording gastro-protection. Carboxymethyl starch (CMS) films were obtained by casting of aqueous filmogenic starch solutions with or without plasticizers and their structural organization was followed using Fourier transform infrared (FTIR), Thermogravimetric analysis (TGA), X-ray diffraction (XRD). Together with data from mechanical tests (tensile strength, elongation, Young's modulus) the results were used to select filmogenic formulations adapted for coatings of tablets. The behaviour of these films was evaluated in simulated gastric and intestinal fluids. The effect of plasticizers (glycerol and sorbitol) on the starch organization, on the rate of drying of the films and on the water vapor absorption was also analyzed. Various types of starch have been compared and the best results were found with high amylose starch (HAS) that was carboxymethylated in an aqueous phase to obtain carboxymethyl high amylose starch (CMHAS). The CMHAS coating solutions containing sorbitol or glycerol as plasticizers have been applied with an industrial pan coater and the final tablets exhibited a good gastro-resistance (up to 2h) in simulated gastric fluid followed by disintegration in simulated intestinal fluid (SIF). The CMHAS derivatives present a high potential as coatings for nutraceutical and pharmaceutical solid dosage forms.

Comparation between fluid bed granulation and high shear mixer as a techniques of choice for achieving optimum homogeneity for low dose solid pharmaceutical dosage form

Comparation between fluid bed granulation and high shear mixer as a techniques of choice for achieving optimum homogeneity for low dose solid pharmaceutical dosage form

Bahan Tambahan dalam Sediaan Tablet: Review

Tablets are solid pharmaceutical dosage form without or with suitable excipients by press or compression manufacturing process. The excipient chosen can influence the product performance (physical properties and stability) and bioavailability. All excipients must be optimally selected to get the optimal formula of tablet dosage form. This article review aims to overview of excipient in tablet dosage form and their role in formulating tablet dosage form. this review article was written based on literature studies from electronic databases such as PubMed, ScienceDirect, and Google Scholar which contain related information using keyword in Indonesian or English use article published in 2013-2023. excipients in tablet dosage form are fillers or diluents, disintegrants, lubricants, preservatives, flavors, sweeteners, coloring, and coating agents. These excipients added to tablet dosage form to facilitating the process of manufacture tablet dosage form, increasing stability and effectiveness of active pharmaceutical ingredients in tablet. The conclusion of this review, there are many classification of tablet excipients which is different function to get compendial requirements of tablet dosage form.

Technology Transfer and Process Validation of Metformin Hydrochloride Immediate Release Tablet

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

Review Article on Inprocess Problems and Evaluation Tests of Tablets Manufacturing

Tablets are the traditional over all medicinal dosage forms for solid dosages. A tablet is a solid pharmaceutical dosage form that is typically manufactured by compressing or moldings the medicinal component with appropriate diluents. They are easier to create than any other dosage form, but during manufacturing, a number of issues may occur that force the batch to be discarded. Post compression studies are also crucial before the dosage forms are put on the market. Modern standards and concepts that emphasize bioavailability, bioequivalence, and validation, among other things, have an impact on formulation design and production. In this article, we discussed the issues (Picking, Sticking, Mottling, etc.) that will arise during the production of tablets, their solutions, as well as the pre- and post- Compression qualities (such as hardness, thickness, and weight variation) and the upper limitations of their use in commercial dosage forms.

Quantitative study ternary mixture of paracetamol, ibuprofen and caffeine in solid pharmaceutical dosage forms by ratio ultraviolet spectroscopy

This paper aims to apply ratio ultraviolet spectroscopy to determine the concentration of substances in a ternary mixture containing paracetamol (PA), ibuprofen (IBU), and caffeine (CA) without chemical treatment, the solvent used in the analysis is a mixture of ethanol with water friendly to environment and safety for users. The ratio ultraviolet spectroscopy method is based on the difference between the peak amplitude of the proportional spectrum at two wavelengths to build regression equations and analytical parameters. The two wavelengths selected in the ratio spectrum for PA, IBU, CA are 246 and 275 nm, 218 and 245 nm, 244 and 278 nm, respectively. The linear range for PA and IBU is 4-40 μg/ml, and for CA, it is 0.8-8 μg/ml; limit of detection (LOD) and limit of quantification (LOQ) of PA, IBU, CA were 0.78, 1.18, 0.38 μg/ml and 2.37, 3.59, 1.17 μg/ml, respectively. The ratio ultraviolet spectroscopy method has successfully determined the concentrations of three substances in a mixture of laboratory and commercial drugs.

Experimental determination and computational prediction of blend time in the USP dissolution testing Apparatus 1

The USP Apparatus 1 (rotating basket) is a preferred testing tool to evaluate the in vitro dissolution performance of pharmaceutical oral solid dosage forms, both as a quality control tool and to determine optimal drug formulations. The test relies on taking samples from the dissolution vessel during the dissolution process to obtain drug dissolution-time profiles. Of significant importance is the determination of the blend time, i.e., the time needed for the drug substance released from the dosage form to become dispersed throughout the vessel, especially at the sampling point. How representative these samples are with respect to the amount of drug dissolved can vary depending on operating and geometrical parameters. Here, the blend time in the USP Apparatus 1 was obtained experimentally and computationally for different operating conditions (basket mesh size, liquid fill volume, and rotation intensity) using the discoloration method coupled with image processing and by conducting time-dependent simulations using the Lattice-Boltzmann Large-Eddy Simulation approach. The experimental and predicted blend times were found to be in agreement. Additionally, an empirical correlation for blend time was developed. These results will help practitioners determine the effect of operating parameters on how representative the samples taken during the test are.

A stability indicating RP-HPLC method development and validation for simultaneous quantification for assay of rifampicin in pharmaceutical solid dosage form

A cost effective stability indicating reverse phase high performance liquid chromatography (RP-HPLC) for simultaneous quantification for assay of Rifampicin in pharmaceutical solid dosage form (tablets) was developed and validated. Chromatographic procedure was conducted using stationary phase packing c18 column (Luna), having 5 µm particle size with inner diameter (250 x 4.6) mm, mobile phase consists of 60% acetate buffer (pH 4.5) and 40% acetonitrile (HPLC grade of sharlau manufacturer). The detection wavelength was uv 254 nm with flow rate of 1.0 ml/min and injection volume was 10 µL with run time 10 min. Based on proposed method validation was conducted following system precision, specificity or selectivity, method precision, accuracy, linearity, robustness, solution stability, limit of quantitation (LOQ), limit of detection. It was observed the system (Waters, HPLC) was precise enough to quantify Rifampicin, no interference of blank, placebo or other known impurity at the elution zone of Rifampicin; % RSD for six sample solutions of Rifampicin was 0.9% (% average assay: 98.7%); accuracy observed 101.1% for 80% recovery, 100.4% for 100% recovery and 100.5% for 120% recovery; co-relation coefficient of linearity (r =1.000); limit of quantification (LOQ) found 0.18 ppm.

Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy

We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM using infrastructure originally intended for batch operations. Consistent with lean manufacturing principles, we select equipment, facilities, and novel process analytical technologies that meet production agility goals alongside an existing batch process. Choices address process risks, are aligned with existing quality systems, yet allow exploration of CM agility benefits in commercial operations. We outline how operating procedures, control schemes, and release criteria from the historical batch process are adapted for CM with modified lot and yield definitions based on patient demand. We devise a hierarchy of complementary controls including real-time process interrogation, predictive residence time distribution models of tablet concentration, real-time product release testing using automated tablet NIR spectroscopy, active rejection and diversion, and throughput-based sampling. Results from lots produced under normal operational conditions confirm our CM process provides assurance of product quality. Qualification strategies to achieve lot size flexibility aims are also described. Finally, we consider CM extensions to formulations with differing risk profiles. Further analysis of results for lots produced under normal operational conditions is provided in part 2 (Rosas et al., 2023).

Micro-Injection Moulding of PEO/PCL Blend–Based Matrices for Extended Oral Delivery of Fenbendazole

Fenbendazole (FBZ) is a broad-spectrum anthelmintic administered orally to ruminants; nevertheless, its poor water solubility has been the main limitation to reaching satisfactory and sustained levels at the site of the target parasites. Hence, the exploitation of hot-melt extrusion (HME) and micro-injection moulding (µIM) for the manufacturing of extended-release tablets of plasticised solid dispersions of poly(ethylene oxide) (PEO)/polycaprolactone (PCL) and FBZ was investigated due to their unique suitability for semi-continuous manufacturing of pharmaceutical oral solid dosage forms. High-performance liquid chromatography (HPLC) analysis demonstrated a consistent and uniform drug content in the tablets. Thermal analysis using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) suggested the amorphous state of the active ingredient, which was endorsed by powder X-ray diffraction spectroscopy (pXRD). Fourier transform infrared spectroscopy (FTIR) analysis did not display any new peak indicative of either a chemical interaction or degradation. Scanning electron microscopy (SEM) images showed smoother surfaces and broader pores as we increased the PCL content. Electron-dispersive X-ray spectroscopy (EDX) revealed that the drug was homogeneously distributed within the polymeric matrices. Drug release studies attested that all moulded tablets of amorphous solid dispersions improved the drug solubility, with the PEO/PCL blend-based matrices showing drug release by Korsmeyer-Peppas kinetics. Thus, HME coupled with µIM proved to be a promising approach towards a continuous automated manufacturing process for the production of oral solid dispersions of benzimidazole anthelmintics to grazing cattle.

UPDATES AND CHALLENGES OF TABLETS

The study of medicine is both a science and an art. There are no compounded pills in it. And bandages; it addresses life's fundamental processes, which must be comprehended before they may be directed. Pharmaceutical oral solid dosage forms have been utilised extensively for decades, mostly due to their ease of administration and suitability for systemic drug delivery. The tablets may be produced directly from powders, granule pellets, or multiple units covered in film. Nowadays, tablets are the most widely used dosage form, making up over 70% of all manufactured ethical pharmaceutical formulations. Tablets are solid pharmaceutical dosage forms that can be moulded or compressed and contain medicinal ingredients with or without appropriate diluents. Tablets can therefore be essentially divided into two categories: compressed tablets and moulded tablets. Directly compressible tablets, chewable tablets, and tablet triturates, among others, are further categories for compressed tablets.

Application of design space and quality by design methodologies combined with ultra high-performance liquid chromatography for the optimization of the sample preparation of complex pharmaceutical dosage forms

Accurate and precise analytical measurements play a significant role in assessments and decisions that are made throughout the drug development process. Developing a robust and reliable sample preparation is essential for drug product formulations to generate consistent results guaranteeing the product quality. However, due to the complex nature of the different pharmaceutical formulations with diverse excipients, developing robust sample preparation methods can be challenging and time consuming. Ensuring sample extraction robustness of pharmaceutical dosage forms becomes increasingly important with the potential impact to patient safety, product efficacy, and business efficiency. In this work we demonstrate and evaluate potential application of Quality by Design (QbD) principles to develop and optimize a robust sample preparation method in combination with the chromatographic analytical technique for a solid pharmaceutical dosage form. Practicability and utility of a QbD approach in optimization of sample preparation of this drug product are demonstrated as the active pharmaceutical ingredient (API) used in the drug product is proven to be highly sensitive for hydrolysis during analysis. Finally, the ultra-high-performance liquid chromatography method with UV detection that was applied during the design of experiments (DoE) was validated as per regulatory requirements. This systematic approach in analytics could provide guidance for the pharmaceutical industry in the development of robust sample preparation methods for different pharmaceutical dosage forms thus significantly reduce risks associated with the method transfers at clinical and commercial manufacturing sites.

Trace Aldehydes in Solid Oral Dosage Forms as Catalysts for Nitrosating Secondary Amines

Nitrosamine impurities may form during drug substance manufacturing processes. Here, we focus on nitrosamine impurity level growth in oral drug products during long term stability studies. Nitrosamine growth mechanisms in oral dosage forms are typically framed as due to nitrosating agents that can be formed in solutions of nitrous acid with a required pH value of around pH 5 or below. We strive in this work to bring awareness to pharmaceutical scientists that formaldehyde, common in oral dosage form excipients, has previously been shown in solution to catalyze the reaction between secondary amines and nitrite ion to give nitrosamine products. This mechanism operates at pH ∼6 and higher. We attempt to re-frame the solution work as relevant to pharmaceutical solid dosage forms. Recent examples of solid dosage form product recalls are used to demonstrate the formaldehyde catalyzed nitrosation pathway operating in the solid state.