Functionality Of Excipients Research Articles

Polyoxylglycerides and glycerides: Effects of manufacturing parameters on API stability, excipient functionality and processing

Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation.

Fuzzy Logic-Based Expert System for Evaluating Cake Quality of Freeze-Dried Formulations

Freeze-drying of peptide and protein-based pharmaceuticals is an increasingly important field of research. The diverse nature of these compounds, limited understanding of excipient functionality, and difficult-to-analyze quality attributes together with the increasing importance of the biosimilarity concept complicate the development phase of safe and cost-effective drug products. To streamline the development phase and to make high-throughput formulation screening possible, efficient solutions for analyzing critical quality attributes such as cake quality with minimal material consumption are needed. The aim of this study was to develop a fuzzy logic system based on image analysis (IA) for analyzing cake quality. Freeze-dried samples with different visual quality attributes were prepared in well plates. Imaging solutions together with image analytical routines were developed for extracting critical visual features such as the degree of cake collapse, glassiness, and color uniformity. On the basis of the IA outputs, a fuzzy logic system for analysis of these freeze-dried cakes was constructed. After this development phase, the system was tested with a new screening well plate. The developed fuzzy logic-based system was found to give comparable quality scores with visual evaluation, making high-throughput classification of cake quality possible.

Co-Processed Excipients: A Patent Review

The introduction of high speed tableting machines and the preference of direct compression as a method of tableting have increased the demands on the functionality of excipients mainly in terms of flowability and compressibility. Co-processed excipients, where in, excipients are combined by virtue of sub-particle level interaction have provided an attractive tool for developing high functionality excipients. The multifold advantages offered by co-processed excipients such as production of synergism in functionality of individual components, reduction of company's regulatory concern because of absence of chemical change during co-processing and improvement in physico-chemical properties have expanded their use in the pharmaceutical industry. In the recent years, there has been a spurt in the number of patents filed on co-processed excipients. Hence, the present review focuses on co-processed excipients and their application in pharmaceutical industry. The worldwide databases of European patent office (http://ep.espacenet.com) and United States patent office (www.uspto.gov) were employed to collect the patents and patent applications. The advantages, limitations, basis for the selection of excipients to be co-processed, methods of co-processing and regulatory perspective of co-processed excipients are also briefly discussed.

Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication

Purpose: To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation.Methods: A model poorly soluble drug was formulated using high shear aqueous granulation. A D-optimal design was used to evaluate and model the effect of granulation conditions, size of milling screen, SLS and Mg.St levels on tablet compaction and ejection. The compaction profiles were generated using a Presster© compaction simulator. Dissolution of the kernels was performed using a USP dissolution apparatus II and intrinsic dissolution was determined using a stationary disk system.Results: Unlike kernels dissolution which failed to discriminate between tablets prepared with various SLS contents, the intrinsic dissolution rate showed that a SLS level of 0.57% was sufficient to achieve the required release profile while having minimal effect on compaction. The formulation factors that affect tablet compaction and ejection were identified and satisfactorily modeled. The design space of best factor setting to achieve optimal compaction and ejection properties was successfully constructed by RSM analysis.Conclusions: A systematic study design helped identify the critical factors and provided means to optimize the functionality of key excipient to design robust drug product.

Recovery of BCS Class II drugs during aqueous redispersion of core–shell type nanocomposite particles produced via fluidized bed coating

Incorporation of BCS Class II drug nanoparticles into solid dosage forms entails drying of nanosuspensions as an intermediate step, which can unfortunately lead to loss of their large surface area through size growth and/or agglomeration. Ensuing incomplete nanoparticle recovery and redispersion during dissolution of the solid dosage forms may lead to poor bioavailability. In this study, nanoparticle recovery from nanocomposite microparticles redispersed in water or an aqueous surfactant solution was investigated as a function of various excipients. Nanosuspensions of griseofulvin (GF), considered as a model BCS Class II drug, were prepared by wet media milling and subsequently dried through coating on Pharmatose® carrier particles in a fluidized bed processor. A polymer (hydroxypropyl cellulose, HPC), a surfactant (sodium dodecyl sulfate, SDS), and their combinations at various concentrations were used as stabilizers during milling; mannitol was used as dispersant in one formulation. The core–shell type nanocomposite microparticles obtained from the fluidized bed coating were redispersed in water using various methods of agitation to recover the GF nanoparticles. Particle size analysis, SEM imaging, and dissolution testing were used to elucidate the redispersion phenomenon and its relevance to dissolution. It was found that the presence of SDS was critical to the full recovery of nanoparticles and their dissolution, whereas HPC appeared to have positive yet convoluted effects. The redispersion methods studied had a slight impact on the recovery of nanoparticles when SDS was present either in the formulation or in the redispersion medium (water). Incomplete recovery of the nanoparticles caused relatively poor drug dissolution, signifying the importance of complete redispersion. The HPC–SDS combination resulted in a synergistic effect in the formation of finer nanoparticles as well as in fast redispersion of GF nanoparticles from the nanocomposite microparticles. A similar redispersion response was observed with another BCS Class II drug, phenylbutazone (PHB).

Coprocessing of cellulose II with amorphous silicon dioxide: effect of silicification on the powder and tableting properties

Aim: In recent years, coprocessing has been the most successful approach to improve and correct the functionality of excipients. The aim of this study is to coprocessed cellulose II with SiO2 and to evaluate the resulting powder and tableting properties.Methods: Novel cellulose II:SiO2 (98:2, 95:5, 90:10 and 80:20 w/w ratios) composites were produced by spray drying, wet granulation and spheronization techniques and the resulting powder and tableting properties were assessed.Results: Cellulose II:SiO2 composites produced by spray- drying exhibited spherical/oblongate shape, narrow distribution and mean diameter from 51 to 75 µm. The composites produced by wet granulation had larger distribution, granular shape and a mean diameter from 105 to 129 µm. The spheronized composites showed the highest size (from 148 to 450 µm) and round shape. Bulk and tap densities and flow were reduced as the silicification level increased in the spray dried and wet granulated materials. Likewise, silicification increased the true density, porosity and surface roughness of these materials. Water sorption decreased only at silicification level of 20% being comparable to the ones shown by Prosolv® samples. Contact angles of all cellulose II materials were lower than those of cellulose I except for Celphere203 indicating better wettability. A 5% and 10% silicification levels rendered the strongest compacts for the spray dried and wet granulated materials, respectively. Silicification did not affect the fast disintegration properties of MCCII.Conclusions: Coprocessing proved to be useful tool to modify the powder and tableting properties of cellulose II.

Direct Compression High Functionality Excipient Using Coprocessing Technique: A Brief Review

Tablets are still the most commonly used dosage form because of the ease of manufacturing, convenience in administration, accurate dosing and excellent stability. Direct compression is the preferred method for the preparation of tablets. However, it has been estimated that less than 20 percent of the active pharmaceutical ingredients (API) can be processed into tablets via direct compression since the majority of API lack the flow, cohesion or lubricating properties required for direct compression. Increasing trends toward direct compression suggests the need for development of high functional excipients. High functionality of excipients can be obtained by development of new excipients or by particle engineering of existing excipients. Particle engineering using coprocessing provides a way to obtain an excipient with high functionality. Coprocessed excipients are the mixture of two or more excipients interacting at sub-particle level; that can provide an excipient with improved functionality as well as masking undesirable properties. Coprocessing is very cost effective method of providing high functional excipient. The present review discusses the advantages of coprocessed excipients, role of material science in coprocessing, methods of coprocessing of excipients and properties of various coprocessed excipients available in the market.

Elucidating Raw Material Variability—Importance of Surface Properties and Functionality in Pharmaceutical Powders

The purpose of this study is to illustrate, with a controlled example, the influence of raw material variability on the excipient's functionality during processing. Soluble starch was used as model raw material to investigate the effect of variability on its compaction properties. Soluble starch used in pharmaceutical applications has undergone a purification procedure including washing steps. In this study, a lot of commercially available starch was divided into two parts. One was left intact and the other was subjected to an extra washing step. The two resulting lots were subjected to a series of physical characterization tests typical of those used to qualify raw materials. The two resulting lots gave virtually identical results from the tests. From the physical testing point of view, the two lots can be considered as two equivalent lots of the same excipient. However, when tested for their functionality when subjected to a compaction process, the two lots were found to be completely different. The compaction properties of the two lots were distinctly different under all environmental and processing conditions tested. From the functionality point of view, the two lots are two very different materials. The similar physical testing results but different functionality can be reconciled by considering the surface properties of the powders. It was found that the washing step significantly altered the surface energetic properties of the excipient. The washed lot consistently produced stronger compacts. These results are attributable to the measurably higher surface energy of induced by the additional washing step.

Investigation of hydrogel isolated from seeds ofOcimum basilicumas binder

Ayurvedic powders are widely used as therapeutic agents but most of them have unpleasant taste and large doses. One of the possible approach to overcome these drawbacks is to represent them in unit dosage form i.e. tablet dosage form. The purpose of this study is to elucidate and quantify the compressibility and compactibility of herbal granules prepared by using hydrogel isolated from whole seeds of Ocimum basilicum as a novel binder. The compressibility is the ability of the powder to deform under pressure and the compactibility is the ability of a powder to form coherent compacts. To test the functionality of novel excipients, Sonnergaard proved a simple linear model to confirm compactability, which is an uncomplicated tool for quantification. The tablets were compressed at increasing compression pressures and were evaluated for various mechanical properties. The linear relationship between specific crushing strength and compression pressure revealed the compactibility of the herbal granules and the linear relationship between porosity and logarithm of compression pressure revealed the compressible nature of the herbal granules according to the model developed by Sonnergaard. Thus the hydrogel isolated from whole seeds of Ocimum basillicum had potential as a granulating and binding agent.

Factors Affecting Defining the Quality and Functionality of Excipients Used in the Manufacture of Dry Powder Inhaler Products

The successful manufacture of a regulatory approved dry powder inhaler (DPI) product is only achievable by applying robust control systems to all aspects of analytical, engineering, and material based processes. Whilst many aspects of DPI drug product manufacturing can be adequately controlled, it is often the control of materials, that is, drug substance and excipients, which can lead to variation in the quality of the final drug product. This article gives an overview of DPI excipients and highlights the challenges of defining and, importantly, understanding the relationships between quality and functionality for excipient components in DPI formulations.

Thermodynamic Properties of Surfactant/Polymer/Water Systems with Respect to Clustering Adsorption and Intermolecular Interaction as a Function of Temperature and Polymer Concentration

This investigation forms part of a more extensive physicochemical study of the interaction of amphiphiles with different polymers, partially as a background for a better understanding of the function of pharmaceutical excipients. For the ethyl hydroxyethyl cellulose (EHEC)/sodium dodecyl sulfate (SDS)/water system, the dialysis equilibrium between a solution containing polymer and a solution not containing polymer has been investigated over a composition interval of the amphiphile ranging from zero up to well above cmc and for the polymer from zero up to slightly above the concentration of critical overlap. It is found that the amphiphile begins to redistribute preferentially to the polymer at a “foot point” (critical aggregation concentration) concentration of 2 mM SDS, rises to a maximum value at an SDS concentration most likely corresponding to the onset of formation of normal micelles in bulk, and then decreases. The maximum adsorption corresponds to approximately two DS- ions per structural unit of the polymer. It is proposed that the results observed could be interpreted in terms of a redistribution of surfactant to the polymer coil regions leading to locally enhanced surfactant concentration, cluster formation, and adsorption. In combination with polymer reconformation this model suggests an explanation of some specific effects observed on this system: the increase in average cluster size with increasing polymer concentration, the marked decrease in intrinsic viscosity at the onset of surfactant adsorption combined with a strong hydrodynamic interaction (high value of the Huggins' constant), and the considerable increase in macroscopic viscosity during the first phase of adsorption. The decrease in specific adsorption after the maximum probably derives from changes in DS- ion activity and saturation of the polymer, as well as the formation of normal micelles. Temperature is found to have only a small influence on the redistribution in an interval from room temperature up to the cloud point. The correction for the Donnan effect is discussed and results from conductometric measurements are used to calculate the degree of dissociation of surfactant in the micellar clusters.

The Past, Present, and Future of Tableting Technology

The evolution of tableting technology was briefly reviewed and the predictions and suggestions for the future of this field were made. The factors that would be primarily responsible for the progress in the development of the justified formulations and processes of the future were pointed out to be dependent on the successful implementation of the following concepts: universal excipient harmonizations; standardized excipient functionality testing; compaction data bank; preformulation database; formulation and process expert systems; a new generation of tableting equipment; and interactive electronic reports. A case study on the use of an integrated compaction research system to evaluate the performance of customized punch displacement profiles was briefly discussed. A special emphasis was given to the first-time application (in the field of pharmaceutical technology) of a prototype interactive electronic data reporting method. Two short communication case studies were presented using the data obtained from milling and compaction studies in order to demonstrate the potential usefulness of the interactive digital data communication in the area of solid-dosage forms.

Development Pharmaceutics and process Validation

AbstractA resume is presented of the guideline on the data required under Part I.A.4. of the Annex to European Directive 75/318/EEC covering the choice of composition of a medicinal product, supported by data on development pharmaceutics. The broad areas of development studies cover the function and compatibility of active ingredients and excipients, the development of liquid, semi-solid and solid dosage forms and the suitability of containers.The guideline aims also to cover general aspects of process validation. The principles laid down in the Guideline are compared with those of FDA guideline on process validation which are much more detailed, but share the same overall aim.One of the fundamental aims of the regulatory control of medicinal products is to ensure the correct purity, potency and consistency of manufacture of each product according to the quality appropriate for its intended use. While Good Manufacturing Practice is essential for quality assurance, other factors such as product design and ...