High Active Pharmaceutical Ingredient Research Articles

NON-NEWTONIAN SUSPENSION FORMULATIONS FOR IMPROVED STABILITY AND DELIVERY OF AUTOINJECTABLE CBRN COUNTERMEASURES

Summary Autoinjectors are commonly employed by the United States and other countries to deliver emergency therapeutics to counteract the effects of various chemical agent threats, including nerve agents. Autoinjector combination products (autoinjector and drug product) used by the military can have drawbacks, including insufficient thermal stability of drug products, limited aqueous solution concentration of active pharmaceutical ingredients (APIs), and complicated and expensive designs for delivering multiple drugs simultaneously. We have developed a novel Enhanced Formulation (EF) technology that solves these problems, using nanoparticle suspensions in biocompatible cottonseed oil (CSO) instead of aqueous solutions of API. The hydrophobic CSO prevents hydrolytic degradation by limiting exposure to water, and the noninteraction of co-suspended particles simplifies multi-drug cocktail therapies. The high API loading (10% or more) gives the formulations non-Newtonian rheological behavior, with high zero-shear viscosity to resist sedimentation, and shear thinning to allow injection with standard autoinjectors and needles.

In-line quantification of two active ingredients in a batch blending process by near-infrared spectroscopy: Influence of physical presentation of the sample

The aim of this study was to apply near-infrared (NIR) spectroscopy to the simultaneous in-line monitoring of two active pharmaceutical ingredients (APIs) in a pharmaceutical batch blending process. The formulation under study consisted of a high load API (A1), one polymer, a second API (A2) and one lubricant. Additionally, the effects of the presentation of A1 on the spectral data were evaluated. For this purpose, the high load active was blended either as a cohesive powder or as a free flowing material. For improving the flow behavior of the high load active a melt-granulation (MG) step was performed. The NIR spectra of the high load API (A1) before and after MG showed that the polymer wavelength absorption band was the most affected, this wavelength range was also associated with the water band region. Thus, these frequencies carried information from the melt-granulation process and could be influenced by the water content. For the APIs quantification, independent partial least squares (PLS-1) models for each API were generated. Furthermore, a PLS-2 model was also developed for the simultaneous quantification of each API. The PLS models were used for the in-line blend uniformity monitoring of both APIs.

An innovative floating gastro retentive dosage system: Formulation and in vitro evaluation

Over the years, different formulation technologies intended for gastro retentive dosage delivery were investigated and patented. The aim of this study was to develop an innovative floating gastro retentive dosage form (GRDF). The developed technology induces a low-density dosage form containing high active pharmaceutical ingredient (API) concentration by using a hydrophobic dusty powder excipient under specific conditions. The new dosage form was obtained by state of the art wet granulation manufacturing process. An experimental design using a discrete variable and four mixture variables was conducted in order to optimize API concentration and buoyancy of the new dosage form. An apparatus was developed to measure the apparent density of floating tablet. The GRDF was characterized for apparent density, buoyancy, porosity and dissolution using in vitro experimentations.

Determination of the composition of counterfeit Heptodin [formula omitted] tablets by near infrared chemical imaging and classical least squares estimation

According to the WHO definition for counterfeit medicines, several categories can be established, e.g., medicines containing the correct active pharmaceutical ingredient (API) but different excipients, medicines containing low levels of API, no API or even a substitute API. Obviously, these different scenarios will have different detrimental effects on a patient’s health. Establishing the degree of risk to the patient through determination of the composition of counterfeit medicines found in the market place is thus of paramount importance. In this work, classical least squares was used for predicting the composition of counterfeit Heptodin ™ tablets found in a market survey. Near infrared chemical imaging (NIR-CI) was used as a non-destructive measurement technique. No prior knowledge about the origin and composition of the tablets was available. Good API (i.e., lamivudine) predictions were obtained, especially for tablets containing a high API (close to the authentic) dose. Concentration maps of each pure material, i.e., the API (lamivudine) and the excipients microcrystalline cellulose, sodium starch glycollate, rice starch and talc, were estimated. Below 1% of the energy was not explained by the model (residuals percentage) for every pixel in all 12 counterfeit tablets. The similarities among tablets with respect to the total API percentage determined, as well as the corresponding concentration maps, support the classification of the tablets into the different groups obtained in previous work.

Development of a high drug load tablet formulation based on assessment of powder manufacturability: Moving towards quality by design

The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of ∼19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10g) approaches. Larger batches were subsequently manufactured to confirm predictions.