Stability of Medicines and Novel Approaches for Predicting Drug Stability

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: 10 November 2024 | Viewed by 19141

Special Issue Editors

Departament of Pharmaceutics and Food Technology, School of Pharmacy, University Complutense, Avenida Complutense, 28040 Madrid, Spain
Interests: nanomedicines; microparticles; sustained-release formulations; liposomes; nanoparticles; drug targeting; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals
Pharmaceutics and Food Technology, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
Interests: conventional pharmaceutical dosage forms (tablets, capsules, semisolid and liquid formulations); new controlled release systems (pellets, nanoparticles, microcapsules, microspheres and liposomes) including production and quality control
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stability is a key parameter to consider when preparing pharmaceutical dosage forms. Novel drug delivery systems have been shown to enhance both the chemical and physical stability of drugs, which is of extreme importance in the pharmaceutical industry. Advanced manufacturing techniques such as 3D printing have arisen as a promising technology to prepare extemporaneous compounding formulations. However, stability studies on these formulations are limited and represent a topic worthy of investigation. This Special Issue is focused on understanding the impact of novel drug delivery systems and new drug manufacturing methods on final drug stability. In addition, stability testing using novel methodological approaches such as accelerated predictive stability (APS) or accelerated stability assessment programs (ASAP) will be covered in this issue as an alternative to conventional ICH guidelines, as there is currently little information available regarding prediction of physical stability of amorphous systems as well as biological compounds such as peptides and proteins.

Dr. Dolores R. Serrano
Prof. Dr. Juan José Torrado Durán
Guest Editors

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Keywords

  • stability
  • 3D printing
  • ICH
  • physical stability
  • biologicals

Published Papers (6 papers)

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Research

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19 pages, 3783 KiB  
Article
Investigation of the Impact of Saccharides on the Relative Activity of Trypsin and Catalase after Droplet and Spray Drying
by Johanna Dieplinger, Christina Moser, Gerhard König, Joana T. Pinto and Amrit Paudel
Pharmaceutics 2023, 15(10), 2504; https://doi.org/10.3390/pharmaceutics15102504 - 21 Oct 2023
Viewed by 957
Abstract
While using saccharides as stabilizers for therapeutic protein drying is common, the mechanisms underlying the stabilization during drying remain largely unexplored. Herein, we investigated the effect of different saccharides, trehalose dihydrate (TD), dextran (DEX), and hydroxypropyl β-cyclodextrins (low substitution—HP and high substitution—HPB), on [...] Read more.
While using saccharides as stabilizers for therapeutic protein drying is common, the mechanisms underlying the stabilization during drying remain largely unexplored. Herein, we investigated the effect of different saccharides, trehalose dihydrate (TD), dextran (DEX), and hydroxypropyl β-cyclodextrins (low substitution—HP and high substitution—HPB), on the relative activities of the enzymes trypsin and catalase during miniaturized drying (MD) or spray drying (SD). For trypsin, the presence of saccharides, especially HP, was beneficial, as it significantly improved the enzyme activity following MD. The HPB preserved trypsin’s activity during MD and SD. Adding saccharides during MD did not show a notable improvement in catalase activities. Increasing TD was beneficial during the SD of catalase, as indicated by significantly increased activity. Molecular docking and molecular dynamics simulations oftrypsin with HP or HPB revealed the influence of their substitution on the binding affinity for the enzyme. A higher affinity of HP to bind trypsin and itself was observed during simulations. Experimentally, activity reduction was mainly observed during MD, attributable to the higher droplet temperature during MD than during SD. The activities from the experiments and aggregation propensity from molecular modeling helped elucidate the impact of the size of protein and saccharides on preserving the activity during drying. Full article
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16 pages, 3155 KiB  
Article
Preformulation and Long-Term Stability Studies of an Optimized Palatable Praziquantel Ethanol-Free Solution for Pediatric Delivery
by Giselle Bedogni, Paula Garcia, Katia Seremeta, Nora Okulik and Claudio Salomon
Pharmaceutics 2023, 15(8), 2050; https://doi.org/10.3390/pharmaceutics15082050 - 30 Jul 2023
Cited by 1 | Viewed by 1597
Abstract
To date, the treatment for cysticercosis and neurocysticercosis consists of a single oral intake of praziquantel (5–10 mg/kg), which since it is only available as tablets, hinders its administration to pediatric patients. Praziquantel is a poorly water-soluble drug which represents a challenge for [...] Read more.
To date, the treatment for cysticercosis and neurocysticercosis consists of a single oral intake of praziquantel (5–10 mg/kg), which since it is only available as tablets, hinders its administration to pediatric patients. Praziquantel is a poorly water-soluble drug which represents a challenge for its formulation in solution, particularly for the pediatric population. Thus, this study aimed to develop a palatable solution for praziquantel using pharmaceutical-accepted co-solvent systems. A design of experiments approach was applied to identify the optimal conditions for achieving a suitable amount of praziquantel in solution using co-solvent mixtures. Thus, praziquantel solubility increased from 0.38 up to 43.50 mg/mL in the optimized system. A taste masking assay in healthy human volunteers confirmed a successful reduction of drug bitterness after the addition of selected flavors and a sweetener. Stability studies were also conducted at different temperatures (4, 25, and 40 °C) for 12 months Even though the presence of the three known impurities of praziquantel was observed, their amounts never exceeded the acceptance criteria of the USP. Thus, this novel approach should be considered a valuable alternative for further preclinical studies considering the high prevalence of this infection worldwide. Full article
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12 pages, 1589 KiB  
Article
Guiding Clinical Prescription of Topical Extemporaneous Formulations of Sodium Cromoglycate Based on Pharmaceutical Performance
by Olga González-González, Enrique Leal, Mercedes Martín-Martínez, Liliana Bautista, Maria Paloma Ballesteros, Juan J. Torrado and Dolores R. Serrano
Pharmaceutics 2023, 15(6), 1609; https://doi.org/10.3390/pharmaceutics15061609 - 29 May 2023
Cited by 2 | Viewed by 2091
Abstract
Cromoglycate (SCG) is widely used for allergy processes, and inflammatory states acting as a mast cell membrane stabilizer that inhibits the histamine and mediator release. Currently, SCG topical extemporaneous compounding formulations are prepared in hospitals and community pharmacies, as no industrial fabricated medicines [...] Read more.
Cromoglycate (SCG) is widely used for allergy processes, and inflammatory states acting as a mast cell membrane stabilizer that inhibits the histamine and mediator release. Currently, SCG topical extemporaneous compounding formulations are prepared in hospitals and community pharmacies, as no industrial fabricated medicines are available in Spain. The stability of these formulations is unknown. Additionally, there are no clear guidelines on which concentration and vehicle are more suitable to enhance permeation across the skin. In this work, the stability of commonly prescribed topical SCG formulations in clinical practice was evaluated. Different vehicles commonly employed by pharmacists daily for formulating topical SCG were investigated (Eucerinum, Acofar Creamgel, and Beeler’s base) at different concentrations, ranging from 0.2 to 2%. The stability of topical extemporaneous compounded SCG formulations can be extended for up to three months at room temperature (25 °C). Creamgel 2% formulations significantly improved the topical permeation of SCG across the skin, being 4.5-fold higher than formulations prepared with Beeler’s base. The reason attributed to this performance can be related to the lower droplet size formed upon dilution in aqueous media combined with a lower viscosity, which facilitates its application and extensibility on the skin. The higher the SCG concentration in Creamgel formulations, the higher the permeability across both synthetic membranes and pig skin (p-value < 0.05). These preliminary results can be used as a guide to prompt a rational prescription of topical SCG formulations. Full article
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16 pages, 10007 KiB  
Article
Effect of Primary Packaging Material on the Stability Characteristics of Diazepam and Midazolam Parenteral Formulations
by María José Rodríguez Fernández, Dolores Remedios Serrano Lopez and Juan José Torrado
Pharmaceutics 2022, 14(10), 2061; https://doi.org/10.3390/pharmaceutics14102061 - 27 Sep 2022
Cited by 2 | Viewed by 2339
Abstract
Diazepam and midazolam are formulated in autoinjectors for parenteral administration to decrease seizures in the case of emergency. However, the compatibility of these lipophilic drugs with the primary packaging material is a key part of drug formulation development. In this work, diazepam and [...] Read more.
Diazepam and midazolam are formulated in autoinjectors for parenteral administration to decrease seizures in the case of emergency. However, the compatibility of these lipophilic drugs with the primary packaging material is a key part of drug formulation development. In this work, diazepam and midazolam were packaged in glass syringes as parenteral solutions using two different elastomeric sealing materials (PH 701/50 C BLACK and 4023/50 GRAY). Syringes were stored at three different storage temperatures: 4, 25, and 40 °C. At different time points over 3 years, physical appearance, benzodiazepine sorption on the sealing elastomeric materials, and drug content in solution were assayed. A detailed study on the adsorption profile of both benzodiazepines on the elastomeric gaskets was performed, indicating that the novel rubber material made of bromobutyl derivatives (4023/50 GRAY) is a better choice for manufacturing autoinjectors due to lower drug adsorption. Diazepam showed a better stability profile than midazolam, with the latter solubilised as a hydrochloride salt in an acidic pH that can affect the integrity of the elastomer over time. The amount of drug adsorbed on the surface of the elastomer was measured by NIR and correlated using chemometric models with the amount retained in the elastomeric gaskets quantified by HPLC. Full article
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Review

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26 pages, 5592 KiB  
Review
Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs
by Madhukiran R. Dhondale, Pradip Thakor, Amritha G. Nambiar, Maan Singh, Ashish K. Agrawal, Nalini R. Shastri and Dinesh Kumar
Pharmaceutics 2023, 15(1), 189; https://doi.org/10.3390/pharmaceutics15010189 - 05 Jan 2023
Cited by 11 | Viewed by 3694
Abstract
Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient’s perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the [...] Read more.
Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient’s perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the medicine ineffective and toxic. Moisture content is known to be the leading cause of the degradation of nearly 50% of medicinal products, leading to impurities in solid dose formulations. The polarity of the atoms in an API and the surface chemistry of API particles majorly influence the affinity towards water molecules. Moisture induces chemical reactions, including free water that has also been identified as an important factor in determining drug product stability. Among the various approaches, crystal engineering and specifically co-crystals, have a proven ability to increase the stability of moisture-sensitive APIs. Other approaches, such as changing the salt form, can lead to solubility issues, thus making the co-crystal approach more suited to enhancing hygroscopic stability. There are many reported studies where co-crystals have exhibited reduced hygroscopicity compared to pure API, thereby improving the product’s stability. In this review, the authors focus on recent updates and trends in these studies related to improving the hygroscopic stability of compounds, discuss the reasons behind the enhanced stability, and briefly discuss the screening of co-formers for moisture-sensitive drugs. Full article
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21 pages, 4816 KiB  
Review
Drug Stability: ICH versus Accelerated Predictive Stability Studies
by Olga González-González, Irving O. Ramirez, Bianca I. Ramirez, Peter O’Connell, Maria Paloma Ballesteros, Juan José Torrado and Dolores R. Serrano
Pharmaceutics 2022, 14(11), 2324; https://doi.org/10.3390/pharmaceutics14112324 - 28 Oct 2022
Cited by 35 | Viewed by 7227
Abstract
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and [...] Read more.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3–4-week period and combining extreme temperatures and RH conditions (40–90 °C)/10–90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed. Full article
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