The choice of the best excipients for the formulation of remedies is of vital importance in ensuring the stability and efficacy of the resulting preparations (1). As formulation scientists, it is imperative that the products we develop have acceptable chemical and physical stability during the period of their distribution and storage. It is not uncommon that an active pharmaceutical ingredient (API) will be stable as bulk drug but unstable when blended with the excipients required for formulation of dosage forms. Understanding the reactivity of the API in the solid state when mixed with excipients is critical to commercial formulation development. Because the gathering of real-time stability and compatibility data is impractical in the early stages of development, we must rely on stress testing and accelerated stability methods for predicting ambient condition interactions and rates of degradation. Often such studies will require innovative approaches to minimize the amount of compound used and to maximize the detection of small quantities of degradation products. This chapter will focus on summarizing approaches to designing, measuring, and interpreting solid-state excipient compatibility data.
This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.
A guide for stabilization of pharmaceuticals to oxidation is presented. Literature is presented with an attempt to be a ready source for data and recommendations for formulators. Liquid and solid dosage forms are discussed with options including formulation changes, additives, and packaging documented. In particular, selection of and methods for use of antioxidants are discussed including recommended levels.
In the preceding article, we reported a novel experimental technique, the "photocopy" method, that allowed the first ever measurements of living chain molecular weight distributions (MWDs) in free radical polymerization (FRP) at steady state. The method entails flooding the FRP at some instant with "photoinhibitor" radicals created photochemically from an appropriate precursor using a short laser pulse. These radicals are extremely slow in initiating new living chains, yet they couple with existing ones (and one another) at near diffusion-controlled rates and carry a fluorescent label. The effect is to freeze the growth of and simultaneously label the living chains that existed just before the laser pulse. In this article we first address the issue of photoinhibitor radical addition to monomer (at rate ), which creates new unwanted labeled living chains that distort the labeled living MWD measurements. Being unable to measure by standard methods due to its extremely small value, we have studied the dependence of the total detected amount of labeled chains on the concentration of photoinhibitor radicals produced per pulse. These experiments suggest, albeit indirectly, that pollution should have a small effect when the photoinhibitor molecule di(1-naphthyl, phenyl methyl) sulfone (DNPMS) is used. Second, we present measurements of living chains whose steady state is perturbed by a series of photocopying pulses, applied with a period shorter than the time required to reestablish the steady state. These pulses have a dual role: (i) with each pulse all living chains are removed from the FRP instantly, creating a "vacuum" at t = 0, and (ii) the MWD of the living chains recovering toward steady state is "copied" into a labeled dead MWD. In this "reverse post-effect" experiment, monitoring the concentration ψl(t) and the mean length N̄(t) of living chains as a function of laser period to, allows us to estimate the propagation velocity vp (number of monomers added to a living chain per second) and the mean steady-state living chain lifetime .
Geminate radical pairs are formed from the α-photocleavage of aryl ketones within the supercage of zeolites which has been modified with chiral guest molecules. Herein, we report the supramolecular structure and dynamic control of both enantnantiomeric selectivity and probability of the recombination of the radical pairs.
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We report the structure−activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.
Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.
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