Drug-Excipient Compatibility Studies in Formulation Development: Current Trends and Techniques

The safety, efficacy, quality and stability of a formulation are the cornerstones of any new drug development process. In order to consistently maintain these attributes in a finished dosage form, it is important to have a comprehensive understanding of the physico-chemical characteristics of the active pharmaceutical ingredient (API), as well as all other components (e.g. excipients, manufacturing aids, packaging materials) of the drug product. In a new drug development process, a detailed characterization of the API and other formulation components is usually carried out during the preformulation stage. The preformulation stage involves characterization of several aspects of the API including solubility, dissolution, permeability, polymorph/salt screening, stability (solidstate and solution-state), ionization properties, particle size distribution, API-excipient compatibilities etc. [1]. Excipients are ubiquitous to virtually every pharmaceutical formulation, and facilitate the manufacture, stability, administration, delivery of the API, and/or provide other functionalities to the dosage form. Excipients are used to improve processing (e.g. improving powder flow [2, 3], powder compactibility [4-6] etc.), enhance aesthetics (e.g. identification, branding etc. [7]), optimize product performance (e.g. modified drug-release [8-11]), and/or to facilitate patient compliance (e.g. taste masking [12-15]). They may constitute anywhere from 1 to 99 % of the total formulation mass. Due to the intimate contact of the API with one or more excipients in a formulation, there exists a likelihood of physical and/or chemical interactions between them. Any such interactions may result in a negative impact on the physical, stability or performance attributes of the drug product [16, 17]. The choice of excipients is of crucial importance to avoid these negative effects, and to facilitate the development of a robust and an effective formulation [18-20]. Thus, for a rational selection of excipients, screening of excipient-API compatibility is recognized as an important aspect of formulation development. Moreover, the USFDA’s 21st century current Good Manufacturing Practices (cGMP) initiative and International Council on Harmonization (ICH) Q8 guidelines encourage the pharmaceutical manufacturers to apply Quality by Design (QbD) principles in their drug development process [21, 22]. These guidelines include expectations of a clear understanding of any interactions between the formulation components. Moreover, recent advances in various thermal and non-thermal analytical techniques have led to an improved efficiency in the detection, monitoring and prevention of the incompatibilities early in the drug development process [23, 24]. This article aims to provide a brief overview of the nature of drug-excipient incompatibilities; as well as current trends and techniques used to evaluate these compatibilities in formulation development

Application of Texture Analysis technique in formulation development of lyophilized orally disintegrating tablets containing mannitol, polyvinylpyrrolidone and amino acids

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Orally disintegrating tablets (ODTs) attract a great attention as this easy swallowing dosage form often improves patient compliance. In the current work, orally disintegrating tablets comprising mannitol, polyvinylpyrrolidone (PVP) and an amino acid (alanine, glycine or serine) with various PVP-to-amino acid ratios were formulated. The combination of mannitol and an amino acid was aimed to use the advantages of mannitol, the matrix-supporting and disintegration agent, and to reduce the total amount of sugar/polyol in tablets. Tablets were manufactured by freeze-drying and their properties (appearance, internal structure, disintegration, mechanical and texture properties, moisture uptake, shrinkage, thermal properties) were assessed. In the work, great emphasis was placed on illustrating the applicability of the Texture Analysis of the freeze-dried cakes directly in vials in formulation development. The results show that the appearance, mechanical properties, disintegration and shrinkage of the freeze-dried ODTs depend significantly on the excipient composition with PVP playing the leading role. Partial mannitol replacement with an amino acid has a limited impact on the tablet properties. The presence of an amino acid also has no impact on the PVP-mannitol interaction. The mechanical and texture properties of freeze-dried ODTs depend non-linearly on the PVP content. The transition between the different types of textures occurs in a narrow range of PVP concentrations regardless of the type of amino acid in a formulation. The non-linear effect of PVP on various tablet properties should be taken into account when designing ODT formulations as it can compromise the robustness of the manufacturing process

Predicting the Drug Release Kinetics of Matrix Tablets

In this paper we develop two mathematical models to predict the release kinetics of a water soluble drug from a polymer/excipient matrix tablet. The first of our models consists of a random walk on a weighted graph, where the vertices of the graph represent particles of drug, excipient and polymer, respectively. The graph itself is the contact graph of a multidisperse random sphere packing. The second model describes the dissolution and the subsequent diffusion of the active drug out of a porous matrix using a system of partial differential equations. The predictions of both models show good qualitative agreement with experimental release curves. The models will provide tools for designing better controlled release devices.Comment: 17 pages, 7 figures; Elaborated at the first Workshop on the Application of Mathematics to Problems in Biomedicine, December 17-19, 2007 at the University of Otago in Dunedin, New Zealan

Melt-extruded polyethylene oxide (PEO) rods as drug delivery vehicles: Formulation, performance as controlled release devices and the influence of co-extruded excipients on drug release profiles

The utility of controlled release medication formulations lies in their ability to keep drugs at steady levels in the blood plasma of recipients and within the termini of the maximum and minimum effective therapeutic levels. This avoids the “ups” and “downs” of medication levels within the body which would have been the result had conventional immediate release tablets been administered instead. In the veterinary field, controlled release medications are essential¹ because of the logistical difficulties of administering drugs on a regular (e.g., daily) basis to animals. The chief advantages of controlled release veterinary medications lie in the ease with which they can be administered; decrease in stress for animals, owing to less need for rounding up and frequent dosing; and, most importantly for farmers, the reduced cost of treatment relative to that for a multiple dosage regime

Supercritical fluid coating of API on excipient enhances drug release

A process to coat particles of active pharmaceutical ingredient (API) onto microcrystalline cellulose (MCC) excipient shows promise as a new way to dosage forms showing enhanced drug release. The process consists of a fluidized bed operated at elevated pressure in which API particles are precipitated from a Supercritical Anti-Solvent process (SAS). MCC particles were used as an excipient in the fluidized bed and collect the SAS-generated API particles. Naringin was selected as the model API to coat onto MCC. A number of operational parameters of the process were investigated: fluidization velocity, coating pressure, temperature, concentration of drug solution, drug solution flow rate, drug mass, organic solvent, MCC mass and size and CO2-to-organic solution ratio. SEM and SPM analyses showed that the MCC particle surfaces were covered with near-spherical nanoparticles with a diameter of approximately 100–200 nm, substantially smaller than the as-received API material. XRD showed that naringin changed from crystalline to amorphous during processing. The coated particles resulting from the SAS fluidized bed process have a higher loading of API, gave faster release rates and higher release ratios in comparison with those produced using a conventional fluidized bed coating process. The approach could be transferred to other industries where release is important such as agrochemical, cosmetic and food

Influence of variability in starting materials quality on stability of finished drug products: a quality-by-design factor and response

The use of ill selected excipients in drug formulations can have a significant influence on the overall stability. Therefore, evaluation of chemical and physical excipient compatibility with the API has become a major part in the development of new drug products. Moreover, general and individual limits for excipient impurities have also been set by the Ph. Eur. However, batch to batch variability of these excipient impurities, although still Ph. Eur compliant, can cause significant variability in the stability profile of finished drug product. Recently, large manufacturer and batch to batch variability in hydroperoxide levels was documented in common used pharmaceutical excipients such as povidone, polysorbate 80, PEG 400 and hydroxypropylcellulose [1]. As a result, oxidation sensitive drugs, e.g. raloxifene HCl, can demonstrate inconsistent stability profiles when combined with aforementioned excipients [2]. Another example in which a miconazole-BHT adduct is formed, can be traced back to the petrolatum vehicle, containing BHT, used for topical application [3]. Note that no BHT limits are mentioned in the corresponding Ph. Eur. monograph. We evaluated the short-term storage stability of three triple intrathecal (Triple IT) solution batches under various conditions [4]. The Triple IT solution, containing cytarabine, methotrexate and methylprednisolone (21)-sodium succinate (MPSS), is used in the treatment of leukemia, lymphoma and brain cancers. Hydrolysis of MPSS to methylprednisolone was found to be the predominant degradation reaction. However, different MPSS degradation kinetics were observed. This observation was linked to the use of different batches of MPSS starting material, i.e. Solu-Medrol®, thus providing an inconsistency in the degradation profile. References [1] Wasylaschuk, W.R.; Harmon, P.A.; Wagner, G.; Harman, A.B.; Templeton, A.C.; Xu, H.; Reed, R.A. Evaluation of hydroperoxides in common pharmaceutical excipients (2006). Journal of Pharmaceutical Sciences; 96; 106-116. [2] Hartauer, K.J; Arbuthnot, G.N.; Baertschi, S.W.; Johnson, R.A.; Luke, W.D; Pearson, N.G.; Rickard, E.C.; Tingle, C.A.; Tsang, P.K.S.; Wiens, R.E. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product (2000). Pharmaceutical Development and Technology; 5; 303-310. [3] Zhang, F.; Nunes, M. Structure and generation mechanism of a novel degradation product formed by oxidatively induced coupling of miconazole nitrate with butylated hydroxytoluene in a topical ointment studied by HPLC-ESI-MS and organic synthesis. [4] D’Hondt, M.; Vangheluwe, E.; Van Dorpe, S.; Boonen, J.; Bauters, T.; Pelfrene, B.; Vandenbroucke, J.; Robays, H.; De Spiegeleer, B. Stability of extemporaneously prepared Triple inthrathecal solution of cytarabine, methotrexate and methylprednisolone sodium succinate (in press). American Journal of Health-System Phamacy

Transdermal evaluation of caffeine in different formulations and excipients

Background: The stratum corneum(SC) forms adifficultphysical barrier fordrugs to pass through the skin. Several strategieswere developed to overcome this barrier.Optimization of topical drug formulations by selected excipients may facilitate the penetration of drugs through the SC into the viable skin cells and ultimately into the systemic circulation. Methods: Here, both the influence of two formulations (a classic carbomer-based gel and a novel Pluronic® lecithin organo gel (PLO gel)) and selected excipients (ethanol, propylene glycol, diethylene glycol monoethyl ether, isopropyl myristate (IPM), and water) with or without the penetration enhancer miconazole nitrate on the transdermal penetration characteristics of caffeine were determined using an in vitro Franz diffusion cell setup. Results: Higher fluxes were observed for the carbomer-based gel compared to the PLO gel. Among the commonly used excipients, IPM showed the best penetration enhancing properties, while the presence of the penetration enhancer miconazole nitrate did not significantly alter the apparent skin permeation characteristics for caffeine. Conclusion: The high ethanol percentage in the carbomer-based gel could explain the results as supported by our excipient data.Moreover, IPMcould play a beneficial role in topical formulations as this excipient was responsible for a significant increase in the amount of caffeine penetrated through the skin. No overall statistical significant effect of the presence of miconazole nitrate as a penetration enhancer was observed

Dextran and its potential use as tablet excipient

Dextrans are a class of carbohydrate polymers extensively applied in pharmaceutical applications, particularly as drug conjugate macromolecular carriers or drug delivery systems. These polysaccharides improve the stability of the therapeutics enabling also the control of their release, via either the parenteral and or oral routes. In the latter case, due to their gel forming ability they may have potential as hydrophilic matrix tablets for sustained drug release. In this paper, we investigated the behaviour of different molecular weight (1, 40, 500 and 2300 kDa) dextrans as tabletting excipients. Powder particle size and hygroscopic studies have been reported, together with tabletability, tablet stability and tablet swelling. Moreover we use tramadol as model compound to evaluate the ability of dextrans to control drug dissolution. The results suggest that dextrans with lower molecular weights may be a promising excipient to be used as filler for immediate release tablets, due to their good tabletability and fast dissolution rate, while dextrans with higher molecular weights could be an efficient disintegrant due to their swelling ability