From compressibility to structural investigation of sodium dodecyl sulphate — Part 1: Powder and tablet physico-chemical characteristics

As a part of a study on detergent tablets, investigations were carried out to elucidate the compression behavior of a powdered surfactant, sodium dodecyl sulphate (SDS), based on a comparison with the main component of the formulation, i.e. the chorine provider (DCCNa). The compacted SDS exhibited poor cohesion as well as delayed dissolution whatever the compression pressure. The microscopic observations and the mercury porosimetry measurements both demonstrated that a residual porosity existed in the tablets but the dissolution times were always long. A modification of SDS in contact with water, forming a structure like a gel, probably occurred, inducing the closing of the pores and thereby limiting the water intrusion into the tablets

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

Performance of Tablet Splitters, Crushers, and Grinders in Relation to Personalised Medication with Tablets

Swallowing problems and the required dose adaptations needed to obtain optimal pharmacotherapy may be a hurdle in the use of tablets in daily clinical practice. Tablet splitting, crushing, or grinding is often applied to personalise medication, especially for the elderly and children. In this study, the performance of different types of (commercially available) devices was studied. Included were splitters, screwcap crushers, manual grinders, and electric grinders. Unscored tablets without active ingredient were prepared, with a diameter of 9 and 13 mm and a hardness of 100–220 N. Tablets were split into two parts and the difference in weight was measured. The time needed to pulverise the tablets (crush time) was recorded. The residue remaining in the device (loss) was measured. The powder was sieved to obtain a particle fraction >600 µm and <600 µm. The median particle size and particle size distribution of the later fraction were determined using laser diffraction analysis. Splitting tablets into two equal parts appeared to be difficult with the devices tested. Most screwcap grinders yielded a coarse powder containing larger chunks. Manual and especially electric grinders produced a finer powder, making it suitable for administration via an enteral feeding tube as well as for use in individualised preparations such as capsules. In conclusion, for domestic and incidental use, a screwcap crusher may provide sufficient size reduction, while for the more demanding regular use in hospitals and nursing residences, a manual or electric grinder is preferred

FORMATION OF A PHYSICALLY STABLE AMORPHOUS DRUG COMPLEX

ABSTRACT In this paper we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug a neutral drug and two basic drugs. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However the ball milled material exhibited superior physical stability when compared to the cryomilled material at 40 oC/75% RH. 13C SSNMR investigation of the ball milled material revealed an acid-base reaction between the acidic drug and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As bench-top milling is a lab scale process, a scalable process was developed to make the acidic drug/Neusilin amorphous drug complex using Hot Melt Extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by bench top milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to outperform tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, Neusilin or other similar silicates would be better choices to stabilize amorphous phase than organic polymers

Correlation of solid-state NMR relaxation times to functional properties such as chemical stability and particle size

The purpose of the work presented in this dissertation was to investigate the correlation between the particle size of crystalline active pharmaceutical ingredients (APIs) and their solid-state NMR (SSNMR) proton spin-lattice relaxation times (1H T1) using model compounds. Dicumarol and salicylic acid were selected as model compounds for this study. Crystalline samples of the model compounds containing particles with sizes ranging from 1 &um- 800 &um were prepared by sieving, spray-drying, and anti-solvent precipitation. The physical state and the particle size of the materials prepared were characterized. A model that describes the correlation observed between the 1H T1 time of the dicumarol and the salicylic acid materials and their particle size was proposed. The model was based on the assumption that spin diffusion is the main spin-lattice relaxation mechanism. The way that SSNMR relaxation time measurements could be used to characterize the polydispersity of crystalline powders using physical mixtures of dicumarol was also investigated. A short investigation of the effect of different compaction forces on the homogeneity of formulated tablets of salicylic acid was also conducted. Different 1H T1 times were obtained for salicylic acid at all compaction forces, and heavier compaction forces lead to a larger decrease in 1H T1 time. Finally, the effect of grinding on the chemical stability of a crystalline API gabapentin was investigated. Changes in 1H T1 times of ground crystalline gabapentin Form II were correlated with the chemical stability of the material: samples with shorter 1H T1 times were the least chemical stable. The physical meaning for the reduction in 1H T1 time observed was believed to be both the presence of crystal defects and the decrease in particle size of the material. This research provided evidence that SSNMR can be used to characterize bulk properties as well as molecular level characteristics of pharmaceutical solids. This could improve the characterization of formulated drug products during drug development

Tablets of “Hydrochlorothiazide in Cyclodextrin in Nanoclay”: A New Nanohybrid System with Enhanced Dissolution Properties

Hydrochlorothiazide (HCT), a Biopharmaceutical Classification System (BCS) class IV drug, is characterized by low solubility and permeability, that negatively affect its oral bioavailability, reducing its therapeutic effcacy. The combined use of cyclodextrins (CDs) and nanoclays (NCs) recently proved to be a successful strategy in developing delivery systems able to merge the potential benefits of both carriers. In this work, several binary systems of CDs or NCs with the drug were obtained, using different drug:carrier ratios and preparation techniques, and characterized in solution and in solid state, to properly select the most effective system and preparation method. Then, the best CD (RAMEB) and NC (sepiolite), at the best drug:carrier ratio, was selected for preparation of the ternary system by co-evaporation and emerged as the most effective preparation method. The combined presence of RAMEB and sepiolite gave rise to a synergistic improvement of drug dissolution properties, with a two-fold increase in the amount of drug dissolved as compared with the corresponding HCT-RAMEB system, resulting in an approximately 12-fold increase in drug solubility as compared with the drug alone. The ternary system that was co-evaporated was then selected for a tablet formulation. The obtained tablets were fully characterized for technological properties and clearly revealed a better drug dissolution performance than the commercial reference tablet (Esidrex®)

Processing-Induced Disorder in Pharmaceutical Materials

This chapter focuses on the major types of pharmaceutical processing methods that have been widely reported to produce disordered material either intentionally or unintentionally. Milling is one of the most frequently used unit operations used by the pharmaceutical industry for reducing the particle size of solids. Thermal processing techniques are mainly used for controlling or improving the release and the subsequent bioavailability of an active pharmaceutical ingredient (API). Techniques such as melt-mixing, spray-congealing, sintering, melt-granulation, and hot-melt extrusion (HME) have developed and evolved rapidly for large-scale pharmaceutical production. Solvent-evaporation-based methods are important processing techniques for both raw materials, such as crystallization of the raw drug, and formulation manufacturing in the pharmaceutical industry. The chapter discusses the processing that can potentially induce the formation of the disordered state during the manufacture of formulations. The widely used solvent-evaporation-based processing techniques in pharmaceutical formulation production include spray-drying, freeze-drying, film casting, and film coating