Krishnaswamy Srinivas Raghavan

Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility.

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.

Use of 2,2'-azobis(2-amidinopropane) dihydrochloride as a reagent tool for evaluation of oxidative stability of drugs.

No HeadingPurpose.To study the oxidative degradation of drugs using a hydrophilic free radical initiator, 2,2′-Azobis(-amidinopropane) dihydrochloride (AAPH).Methods.AAPH was used as the free radical initiator to study oxidation of three model compounds (A, B, and C), which represent different oxidizable moieties. In the solution model, the drugs and AAPH were dissolved in a mixture of acetonitrile and aqueous buffer and incubated at elevated temperatures to evaluate oxidative degradation. The effects of pH and drug-AAPH ratio on the kinetics of the reaction were evaluated for compound A. Commonly used antioxidants were also evaluated by addition to solutions of drug and AAPH. In the solid-state model, blends of drug with microcrystalline cellulose were treated with AAPH and placed at elevated temperature and humidity to evaluate solid state oxidation.Results.Use of AAPH resulted in selective oxidation of the model drugs by a free radical initiated process. The scope of the technique was further investigated in detail using compound A. The rate of oxidation of compound A varied directly with the concentration of AAPH. The pseudo first-order rate constants for the oxidative degradation were calculated from the kinetic data. The antioxidants were rank-ordered based on their quenching activity on the rates of AAPH initiated oxidation for compound A. The concept was extended to oxidation in solid state.Conclusions.The proposed AAPH model is useful in assessing oxidative stability of drug candidates in development.

The Effect of Polymeric Excipients on the Physical Properties and Performance of Amorphous Dispersions: Part I, Free Volume and Glass Transition

PurposeTo investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition.MethodsTwo drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions.ResultsThe chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution.ConclusionsBoth the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

A high-throughput spectrophotometric approach for evaluation of precipitation resistance

Many drugs that come out of discovery today are extremely challenging to formulate because of their high hydrophobicity and low water solubility. A kinetic, spectrophotometric approach for the rapid evaluation of precipitation resistance of multiple solubilized formulations that can be run on a very small scale is proposed. Using this high-throughput approach, multiple formulations are screened for inhibition of precipitation upon dilution into an aqueous environment. Data generated using the in vitro spectrophotometric approach is comparable to the traditional chromatographic approaches. Similar approaches have been previously attempted, but in this study, the focus is on pharmaceutical development of solubilized formulations by evaluation of the events post precipitation as opposed to determining the moment at which precipitation is observed, which is usually the case in kinetic solubility measurements. The information garnered thus offers insights not just into amount of precipitation, but also to the size and nature of the precipitate. Overall, this technique offers the potential to change the approach to the development of toxicology vehicles and solubilized clinical formulations for oral administration.

Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

PurposeTo investigate the effect of polymer additives on the transformation of BMS-566394 anhydrate to the dihydrate form and to propose the possible mechanisms for inhibition of conversion of the anhydrate to the dihydrate form.Materials and methodsThe conversion of anhydrate to dihydrate was monitored using differential scanning calorimetry, powder X-ray diffraction and polarized light microscopy. Solubility and intrinsic dissolution studies were performed on anhydrate and dihydrate. IR and NMR spectroscopy were used to probe the molecular interactions between BMS-566394 and cellulose ether polymers.ResultsThe anhydrate form of BMS-566394 was readily transformed into the more stable dihydrate form in aqueous suspension. The kinetic solubility and intrinsic dissolution rate of the anhydrate were ca. fourfold that of the dihydrate. Addition of cellulose ether polymers (HPC, HPMC, MC) inhibited anhydrate to dihydrate transformation in aqueous suspensions. Hydrogen bonding interaction between the polar groups of the drug and polymers was inferred from infrared spectroscopy. Solution NMR also indicated a hydrophobic interaction between the drug and polymer backbone.ConclusionsThe anhydrate form of BMS-566394 is stabilized in the presence of cellulose ether polymers. Spectroscopic evidence is offered to postulate a molecular interaction between drug and polymers.

Understanding drug-excipient compatibility: Oxidation of compound A in a solid dosage form

Drug-excipient compatibility studies lay the foundation for designing a chemically stable formulation for clinical and commercial development. This article describes the investigation of oxidative degradation encountered with compound A (a phenylalanine-drug complex) in a capsule dosage form. Two wet- granulation capsule formulations (2.5-mg and 25-mg strengths) were developed using excipients that showed satisfactory stability from initial drug-excipient compatibility studies. Both capsule strengths were chemically stable at 50°C (closed) for at least 18 weeks, but they showed discoloration. The 2.5-mg capsule exhibited degradation after four weeks at 40°C/75%RH (open) besides discoloration. LC/MS analysis indicated that the degradants were oxidation products of the parent compound. Oxidation of compound A was investigated by forced degradation with peroxide, use of isotopically labeled water (H218O) to study the source of oxygen, and use of different antioxidants to mitigate oxidation. Excipient(s) responsible for oxidation and discoloration were identified through extended and modified excipient compatibility studies. The discoloration was indicative of Maillard reaction occurring between a reducing sugar impurity from microcrystalline cellulose and L-phenylalanine in the drug complex. Reactive oxidative species generated by this reaction is postulated to cause oxidation of compound A.

Chapter 6 – Excipient Compatibility

Publisher Summary The excipient compatibility is related to the physical and chemical stability of the drug in solid dosage forms. Some of the common ways by which excipients may affect drug stability in the dosage form are by altering moisture content in the dosage form, changing microenvironmental pH in the dosage form, acting as general acid–base catalysts, directly reacting with drug or becoming a source of impurities that can either directly react with drug substances or participate as catalysts in the drug degradation. The excipients can also alter the physical and/or the chemical form of the drug through, for example, ion-exchange, transformation of polymorphs, and the formation of eutectic or solid solutions. The changes in physical or chemical state may in turn alter the chemical stability of the drug. Most drugs and excipients contain water, which may be either bound or unbound. The physical state of water in an excipient or the drug–excipient mixture determines its potential role in drug–excipient interactions. Presence of water in the solid-state systems has a significant impact on the stability, not only in causing the hydrolysis of drugs, e.g., of acetylsalicylic acid, but also its participation as a reaction medium, and in increasing the plasticity and molecular mobility of the system.

Phase behavior of TPGS–PEG400/1450 systems and their application to liquid formulation: A formulation platform approach

Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing.

Excipient Compatibility and Functionality

Abstract Excipient selection is based on their functionality, compatibility, and variability of critical material attributes within an acceptable range for a given drug product. Drug-excipient compatibility studies are usually used as a screening tool to identify potential incompatibilities that alter physical, chemical, microbiological, or therapeutic properties of the drug in the dosage form. Excipient functionality involves the identification of critical material attributes based on target material properties and the functionality-related characteristics that impact the in-process and finished product quality attributes. Understanding the mechanistic basis of functional role and the commonly encountered range of variability of excipient attributes helps identify the acceptable range of excipient variability in a given drug product. This chapter describes contemporary practices in the identification of functionality-related characteristics of excipients; compatibility study designs and data interpretation; and understanding excipient variability and its impact on drug product quality attributes with examples and case studies.

Reactive Impurities in Excipients

Reactive impurities in pharmaceutical excipients can affect drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development can ensure robust drug product development. This chapter identifies the type and concentration of potentially reactive impurities in commonly used excipients. The excipient impurities are categorized into six major classes: reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources/generation of these impurities, analytical methods for their detection and quantitation, stability of these impurities upon storage and processing, and their potential reactions with drug candidates are discussed. Specific examples of drug–excipient impurity interaction are presented as illustrative case studies. Mitigation strategies and corrective measures are also discussed.