Polysorbate identity and quantity dictate the extensional flow properties of protein-excipient solutions

While protein medications are promising for treatment of cancer and autoimmune diseases, challenges persist in terms of development and injection stability of high-concentration formulations. Here, the extensional flow properties of protein-excipient solutions are examined via dripping-onto-substrate extensional rheology, using a model ovalbumin (OVA) protein and biocompatible excipients polysorbate 20 (PS20) and 80 (PS80). Despite similar PS structures, differences in extensional flow are observed based on PS identity in two regimes: at moderate total concentrations where surface tension differences drive changes in extensional flow behavior, and at small PS:OVA ratios, which impact the onset of weakly elastic flow behavior. Undesirable elasticity is observed in ultra-concentrated formulations, independent of PS identity; higher PS contents are required to observe these effects than in analogous polymeric excipient solutions. These studies reveal novel extensional flow behaviors in protein-excipient solutions, and provide a straightforward methodology for assessing the extensional flow stability of new protein-excipient formulations.     

Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets

Objective: To investigate the modulation of the wettability of excipients by different types of surfactants and its impacts on the disintegration of tablets and drug release.

Materials and methods: The critical micelle concentration (CMC) of surfactants, including sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), dodecyl trimethyl ammonium bromide (DTAB), cetyltrimethyl ammonium bromide (CTAB) and polysorbate (Tween-20 and Tween-80), was obtained using the platinum ring method. Contact angles of surfactant solutions on the excipient compacts and double-distilled water on the mixture of surfactant and the other excipient (magnesium stearate (MgSt) or sodium alginate (SA)) were measured by the sessile drop technique. Besides, surface free energy of excipients was calculated by the Owens method. Finally, the disintegration of tablets and in vitro dissolution testing were performed according to the method described in USP.

Results and discussion: The wettability of excipients could be enhanced to different extent with low concentration of surfactant solutions and maintained stable basically after CMC. For MgSt (hydrophobic excipient), the shorter the hydrophobic chain (C₁₂, including SDS and DTAB), the better the wettability with the addition of surfactant in the formulation, leading to the shorter disintegration time of tablets and higher drug release rate. In contrast, the wettability of SA (hydrophilic excipient) was reduced by adding surfactant, resulting in the longer disintegration time of tablets and lower release rate.

Conclusion: The modulation of the wetting of pharmaceutical excipients by surfactant had changed the disintegration time of tablets and drug release rate to a greater extent.     

Improving dissolution kinetics of pharmaceuticals by fluidized bed impregnation of active pharmaceutical ingredients

Investigational drugs are increasingly becoming less soluble in aqueous media, thus, presenting real challenges during development. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers. This study demonstrates the usefulness of FB impregnation in formulating poorly soluble drugs. We show that dissolution of Fenofibrate is greatly improved by FB impregnation onto Neusilin^® (Fuji Health Science Inc, Burlington, NJ USA), a synthetic amorphous form of magnesium alumino‐metasilicate. We impregnate Neusilin^® for range of loadings and examine Fenofibrate's physical state. Dissolution of impregnated formulations is drug loading dependent and loadings below 40% show great improvement (decrease) in release time compared to physical blend. Release times are further improved by milling. We also examine feasibility of coimpregnating Fenofibrate with additives and observe stability (1.5 years) of the amorphous form of Fenofibrate inside Neusilin^®. This stabilization significantly improves Fenofibrate's dissolution kinetics, making our formulation comparable to one of the current market formulations, TriCor^® tablets (AbbVie Inc, North Chicago, IL USA). © 2016 American Institute of Chemical Engineers AIChE J, 62: 4201–4214, 2016     

The galenic behaviour of a dermopharmaceutical excipient containing honey

This paper describes the design of an emulsion cream, obtained from a self-emulsifying base, to which lavender honey has been added. Physical, galenic and stability studies and assays, and rheological analyses, are used to describe the qualities and properties of the honeyed cream under study. The formula is presented as an ivory-coloured cream with a light lavender scent and agreeable organoleptic characteristics. From a rheological viewpoint this is very adequate for spreading and applying onto the skin because of its thixotropic behaviour. The emulsion is stable and perfectly adaptable to the requirements of this type of skin application.     

Evaluation about wettability,water absorption or swelling of excipients through various methods and the correlation between these parameters and tablet disintegration

Objective: To evaluate parameters about wettability, water absorption or swelling of excipients in forms of powders or dosage through various methods systematically and explore its correlation with tablet disintegration.

Material and methods: The water penetration and swelling of powders with different proportions of excipients including microcrystalline cellulose (MCC), mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCMC-Na) and magnesium stearate (MgSt) were determined by Washburn capillary rise. Both contact angle of water on the excipient compacts and surface swelling volume were measured by sessile drop technique. Moreover, the test about water absorption and swelling of compacts was fulfilled by a modified method. Eventually, the disintegration of tablets with or without loratadine was performed according to the method described in USP.

Results and discussion: These parameters were successfully identified by the methods above, which proved that excipient wettability or swelling properties varied with the structure of excipients. For example, MgSt could improve the water uptake, while impeded tablet swelling. Furthermore, in the present study it is verified that tablet disintegration was closely related to these parameters, especially wetting rate and initial water absorption rate. The higher wetting rate of water on tablet or initial water absorption rate, the faster swelling it be, resulting in the shorter tablet disintegration time.

Conclusion: The methods utilized in the present study were feasible and effective. The disintegration of tablets did relate to these parameters, especially wetting rate and initial water absorption rate.     

Stability of pharmaceutical salts in solid oral dosage forms

Using pharmaceutical salts in solid dosage forms can raise stability concerns, especially salt dissociation which can adversely affect the product performance. Therefore, a thorough understanding of the salt instability encountered in solid-state formulations is imperative to ensure the product quality. The present article uses the fundamental theory of acid base, ionic equilibrium, relationship of pH and solubility as a starting point to illustrate and interpret the salt formation and salt disproportionation in pharmaceutical systems. The criteria of selecting the optimal salt form and the underlying theory of salt formation and disproportionation are reviewed in detail. Factors influencing salt stability in solid dosage forms are scrutinized and discussed with the case studies. In addition, both commonly used and innovative strategies for preventing salt dissociations in formulation, on storage and during manufacturing will be suggested herein. This article will provide formulation scientists and manufacturing engineers an insight into the mechanisms of salt disproportionation and salt formation, which can help them to avoid and solve the instability issues of pharmaceutical salts in the product design.     

Green isolation and physical modification of pineapple stem waste starch as pharmaceutical excipient

The waste of inedible parts of pineapple, particularly in tropical countries, contributes to environmental burden. This study aimed to utilize pineapple stem waste as a source of starch-based pharmaceutical excipient. The starch was isolated from pineapple stem waste using a simple process without applying harsh chemicals. The isolated starch (PSS) was then physically modified through gelatinization and spray drying to improve its physical properties. Starch characteristics were identified by FTIR, TGA, and XRD analysis. The SEM imaging showed morphological change with reduced surface roughness due to physical modification of the starch. Decreased crystallinity of modified starch (MPS) was confirmed by our XRD results: the peaks of A-type crystalline at 2θ of 13°, 15°, 18°, and 23° were present in PSS, yet mostly absent in MPS. Thermogravimetric analysis showed that MPS behaved differently from PSS and the degradation events occurred at lower temperature. When the starch was spray-dried without prior gelatinization process, the physicochemical characteristics of spray-dried starch resembled untreated starch. Moisture content in PSS (10.66%) decreased after gelatinization to 7.3%. Potential use of MPS was demonstrated by its powder flowability (Student’s t test, p?<?0.05), swelling capacity (Student’s t test, p?<?0.05), and compaction profile. In summary, our findings demonstrated that modified pineapple starch showed better physical characteristics and quite promising as a tablet binder and disintegrant.     

Pharmaceutical Evaluation of Multipurpose Excipients for Direct Compressed Tablet Manufacture: Comparisons of the Capabilities of Multipurpose Excipients with Those in General Use

Recently, a novel type of multipurpose excipient (MPE) with high binding characteristics and high fluidity has been developed. In this study, the capabilities of MPEs (Ludipress and Microcelac) were compared with those of excipients in general use. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by the direct compression method. Multipurpose excipients mixed with adjuvants such as fillers, binders, lubricants, disintegrants, and the like show superior fluidity and compressibility. Tablets containing very small amounts of highly active ingredients with little dispersion were prepared. However, with increases in active ingredient content, each of the physical properties was affected strongly by the properties of the active ingredient. Tablets with appropriate hardness and disintegration characteristics could be prepared by mixing of different types of MPEs.     

The stress stability of olanzapine: studies of interactions with excipients in solid state pharmaceutical formulations

Stress stability testing represents an important part of the drug development process. It is used as an important tool for the identification of degradation products and degradation pathways, as well as for the assessment of changes in physical form of drug molecules. The impact of excipients on the stability of olanzapine confirms that levels of impurities and degradants are limiting parameters and are therefore used for stability evaluation. The major degradation product of olanzapine was identified as 2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepine-4-one (III). The structure of III was determined by using LC-MS, IR and NMR. Compatibility and stress stability results demonstrated that tablet formulations of olanzapine are sensitive to temperature and moisture. In samples protected from moisture, the increase in concentration of III was shown to be highly temperature dependent and the degradation followed zero-order kinetics. In addition, studies of olanzapine with excipients and in formulated tablets revealed polymorphic phase changes in some samples, influenced by a combination of stress temperature and humidity conditions. Polymorphic transitions were monitored using x-ray powder diffraction (XRPD) analysis and exhibited no correlation between the phase change (appearance of a new polymorph) and the degradation process.