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International Journal of Pharmaceutics May 2024Liposomes are widely used in the pharmaceutical industry as drug delivery systems to increase the efficacy and reduce the off-target toxicity of active pharmaceutical... (Review)
Review
Liposomes are widely used in the pharmaceutical industry as drug delivery systems to increase the efficacy and reduce the off-target toxicity of active pharmaceutical ingredients (APIs). The liposomes are more complex drug delivery systems than the traditional dosage forms, and phospholipids and cholesterol are the major structural excipients. These two excipients undergo hydrolysis and/or oxidation during liposome preparation and storage, resulting in lipids hydrolyzed products (LHPs) and cholesterol oxidation products (COPs) in the final liposomal formulations. These excipient-related impurities at elevated concentrations may affect liposome stability and exert biological functions. This review focuses on LHPs and COPs, two major categories of excipient-related impurities in the liposomal formulations, and discusses factors affecting their formation, and analytical methods to determine these excipient-related impurities.
Topics: Excipients; Liposomes; Drug Contamination; Cholesterol; Hydrolysis; Phospholipids; Oxidation-Reduction; Chemistry, Pharmaceutical; Drug Stability
PubMed: 38688429
DOI: 10.1016/j.ijpharm.2024.124164 -
Journal of Pharmaceutical Sciences May 2023The occurrence of N-nitrosodialkylamines in active pharmaceutical ingredients (APIs) and drug products in the last years was a kind of eye opener with regard to quality... (Review)
Review
The occurrence of N-nitrosodialkylamines in active pharmaceutical ingredients (APIs) and drug products in the last years was a kind of eye opener with regard to quality of drugs. We became aware of the fact that quality control tests described in the international pharmacopoeias might not be sufficient. The N-nitrosodialkylamines found were neither so-called (structurally) related substances, nor residual solvents or heavy metals; hence they were not limited by a compendial test, but by the ICH guideline M7 of mutagenic impurities. Additionally, nitrosamine drug-substance-related impurities (NDSRIs) were detected, mostly within the process of risk assessment required by regulatory authorities. Here, the APIs containing a vulnerable amino moiety had reacted with nitrites being a contaminant of an excipient. This review deals with the formation, toxicity, and mitigation of NDSRISs.
Topics: Excipients; Drug Contamination; Nitrosamines; Pharmaceutical Preparations
PubMed: 36720391
DOI: 10.1016/j.xphs.2023.01.021 -
Journal of Pharmaceutical Sciences May 2022Alginates are naturally occurring polymers revealing low toxicity, good biocompatibility and biodegradability, excellent gelling and thickening properties, as well as... (Review)
Review
Alginates are naturally occurring polymers revealing low toxicity, good biocompatibility and biodegradability, excellent gelling and thickening properties, as well as low production cost and good availability. One of the most important features typical for alginates is the ability to undergo ionotropic gelation which is gel formation process occurring upon the contact with cations. Because of their advantageous properties, alginates have been extensively utilized in food and pharmaceutical industries. In this review the current knowledge regarding the most recent studies involving both popularly applied dosage forms, like tablets or hydrogels, and novel advanced drug delivery systems applied in targeted therapies are summarized and discussed. The presented studies indicate that although sodium alginate is a well-established polymer, it is still widely applied as pharmaceutical excipient and the presented research studies indicate that there are still research areas that can be explored and provide innovation in drug delivery systems.
Topics: Alginates; Drug Carriers; Drug Delivery Systems; Excipients; Glucuronic Acid; Hexuronic Acids; Polymers
PubMed: 34986359
DOI: 10.1016/j.xphs.2021.12.024 -
Journal of Pharmaceutical Sciences Mar 2023The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the...
The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the manufacturing process. Therefore, it is imperative that formulators are able to accurately and completely specify the key chemical and physical properties of those excipients. Current approaches to describing excipients are outdated and inadequate for the needs of the 21 century and in this article we highlight the benefits of a more systematic and comprehensive approach to specifying and controlling excipient properties. We hope that this will prompt the users, suppliers, and manufacturers of excipients to take a careful look at current approaches and develop tangible proposals for attaining an enhanced future state.
Topics: Chemistry, Pharmaceutical; Excipients
PubMed: 36526004
DOI: 10.1016/j.xphs.2022.12.003 -
Drug Development and Industrial Pharmacy Feb 2021Amorphization is a well-established strategy to enhance the dissolution properties of poorly water-soluble drugs. However, the amorphous state is inherently unstable...
Amorphization is a well-established strategy to enhance the dissolution properties of poorly water-soluble drugs. However, the amorphous state is inherently unstable toward recrystallization. Coamorphous systems of a drug and a small-molecule excipient or of two complementary drugs often show an enhanced stability. Diabetes and hypertension are frequently coexistent. In this paper a study on the coamorphization of the poorly water-soluble antidiabetic drug gliclazide (glz) and the antihypertensive drug valsartan (val) is reported. Amorphous glz recrystallized after 1 d under ambient conditions, whereas coamorphous glz-val containing glz and val in a 1:1 or 1:2 molar ratio was stable for at least four months at 20 °C and 56% relative humidity. The dissolution rate of glz increased in the order crystalline glz < glz-val_1:1 < glz-val_1:2. Furthermore, ternary coamorphous systems of glz, val and an excipient were prepared; glz-val_1:1_PVP, glz-val_1:1_HPC, glz-val_1:1_ALM, glz-val_1:1_MCC (PVP = polyvinylpyrrolidone, HPC = hydroxypropyl cellulose, ALM = α-lactose monohydrate, MCC = microcrystalline cellulose). MCC and HPC did not affect the stability of the coamorphous system, while ALM promoted the recrystallization of glz in glz-val_1:1_ALM during storage and freshly prepared glz-val_1:1_PVP contained small amounts of crystalline glz. Glz-val_1:1_MCC showed enhanced dissolution properties compared to crystalline glz and glz-val_1:1 and is a viable fixed-dose formulation.
Topics: Drug Stability; Excipients; Gliclazide; Solubility; Valsartan
PubMed: 33492999
DOI: 10.1080/03639045.2021.1879838 -
International Journal of Pharmaceutics Apr 2023The glass-transition temperature and the composition of the amorphous phase/maximally concentrated solution (classically referred to as T' and w', respectively) as...
The glass-transition temperature and the composition of the amorphous phase/maximally concentrated solution (classically referred to as T' and w', respectively) as function of added excipients are crucial for the design of lyophilization processes. Whereas the determination of T' can be accomplished easily using mDSC, the determination of w' poses challenges, since the experimental effort needs to be redone for each new excipient mixture (limited transferability of the results possible). In this work, an approach was developed which allows to predict w' for (1) single excipients, (2) given compositions of a binary excipient mixture, and (3) single excipients in aqueous (model) protein solutions using the thermodynamic model PC-SAFT and one experimental data point of T'. Sucrose, trehalose, fructose, sorbitol, and lactose were considered as single excipients. The binary excipient mixture consisted of sucrose and ectoine. The model protein was bovine serum albumin in combination with sucrose. The results reveal that the new approach can precisely predict w' in the systems considered, including the non-linear course of w' identified for different sucrose/ectoine ratios. The same applies to the course of w' as function of the protein concentration. This newly developed approach allows for the reduction of the experimental effort to a minimum.
Topics: Excipients; Temperature; Serum Albumin, Bovine; Sucrose; Freeze Drying; Calorimetry, Differential Scanning
PubMed: 36940838
DOI: 10.1016/j.ijpharm.2023.122836 -
Pharmaceutical Research Sep 2019Pharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance... (Review)
Review
Pharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance of the product. The understanding of materials' properties and technological processes is a requirement for building quality into pharmaceutical products. Such understanding is gained mostly from empirical correlations of material and process factors with quality attributes of the final product. However, it seems also important to gain knowledge based on mechanistic considerations. Promising is here to study morphological and/or topological characteristics of particles and their aggregates. These geometric aspects must be taken into account to better understand how product attributes emerge from raw materials, which includes, for example, mechanical tablet properties, disintegration or dissolution behavior. Regulatory agencies worldwide are promoting the use of physical models in pharmaceutics to design quality into a final product. This review deals with pharmaceutical applications of theoretical models, focusing on percolation theory, fractal, and multifractal geometry. The use of these so-called fractal approaches improves the understanding of different aspects in the development of solid dosage forms, for example by identifying critical drug and excipient concentrations, as well as to study effects of heterogeneity on dosage form performance. The aim is to link micro- and macrostructure to the emerging quality attributes of the pharmaceutical solid dosage forms as a strategy to enhance mechanistic understanding and to advance pharmaceutical development and manufacturing processes.
Topics: Dosage Forms; Drug Compounding; Excipients; Fractals; Humans; Tablets
PubMed: 31493266
DOI: 10.1007/s11095-019-2685-5 -
The AAPS Journal Jan 2022The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the... (Review)
Review
The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here. Graphical Abstract.
Topics: Animals; Biological Availability; Biopharmaceutics; Drug Compounding; Drug Development; Drug and Narcotic Control; Excipients; Humans; Permeability; Pharmaceutical Preparations; Therapeutic Equivalency
PubMed: 34988701
DOI: 10.1208/s12248-021-00670-1 -
Journal of Food and Drug Analysis Jun 2021Quality control (QC) is the most important key issue in the pharmaceutical industry to ensure the quality of drug products. Many analytical instruments and techniques in... (Review)
Review
Quality control (QC) is the most important key issue in the pharmaceutical industry to ensure the quality of drug products. Many analytical instruments and techniques in pharmaceutical analysis are applied to assess the quality and quantity of the drugs. In the current and future trends, a combination of digitization, automation and hyphenation with high throughput on-line performance will be the topics for the future of pharmaceutical QC. The hyphenated analytical techniques have recently received great attention as unique means to solve complex analytical problems in a short period of time. This review article is an update on the recent potential applications of hyphenated technique developed from the coupling of a rapid separation or induction technique (differential scanning calorimetry; DSC) and an on-line spectroscopic (Fourier transform infrared; FTIR) detection technology to carry out an one-step solid-state analysis in pharmaceutical formulation developments, including (1) intramolecular condensation of pharmaceutical polymers, (2) intramolecular cyclization of drugs and sweetener, (3) polymorphic transformation of drugs and excipients, (4) drug-polymer (excipient) interaction, (5) fast cocrystal screening and formation. This simultaneous DSC-FTIR microspectroscopy can also provide an easy and direct method for one-step screening and qualitative detection of drug stability in real time.
Topics: Calorimetry, Differential Scanning; Drug Stability; Excipients; Spectroscopy, Fourier Transform Infrared
PubMed: 35696204
DOI: 10.38212/2224-6614.3345 -
International Journal of Pharmaceutics Feb 2023The surface of particles is the hotspot of interaction with their environment and is therefore a major target for particle engineering. Particles with tailored coatings...
The surface of particles is the hotspot of interaction with their environment and is therefore a major target for particle engineering. Particles with tailored coatings are greatly desired for a range of different applications. Amorphous coatings applied via film coating or microencapsulation have frequently been described in the pharmaceutical context and usually result in homogeneous surfaces. In the present study we have been exploring the feasibility of coating core particles with crystalline substances, a matter that has rarely been investigated. The expansion of the range of possible coating materials to include small organic molecules enables completely new product properties to be achieved. We present an approach based on temperature cycles performed in a tubular crystallizer to result in engineered crystalline coatings on excipient core particles. By manipulating the process settings and by the choice of coating substance we are able to tailor surface roughness, topography as well as surface chemistry. Benefits of our approach are demonstrated by using resulting particles as carriers in dry-powder-inhaler formulations. Depending on the resulting surface chemistry and surface roughness, coated carrier particles show varying fitness for delivering the model API salbutamol sulphate to the lung.
Topics: Drug Carriers; Temperature; Particle Size; Powders; Administration, Inhalation; Albuterol; Dry Powder Inhalers; Excipients; Surface Properties
PubMed: 36596318
DOI: 10.1016/j.ijpharm.2022.122577