The relationships among Flory-Huggins specific interaction parameters, maximum amorphous capacity, and solid-state interactions of spray dried amorphous drug dispersions with conventional and novel pharmaceutical polymers / Las relaciones entre los parámetros de interacción específicos de Flry-Huggins, la capacidad amorfa máxima y las interacciones en estado sólido de las dispersiones de fármacos amorfos secados por aspersión con polímeros farmacéuticos convencionales y nuevos

This study evaluated the specific interactions between drug and polymers in amorphous spray dried dispersions (SDDs). Four Biopharmaceutics Classification System (BCS) II class drugs were evaluated. Binary and ternary SDDs were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between drug and polymer were determined using theoretical calculations and DSC data. Analytical methods were used to evaluate solid and solution state interactions. Maximum amorphous content for each formulation was calculated using DSC. Flory-Huggins Specific Interaction Parameters were calculated. Negative specific parameters were associated with solid-state interactions and improved capacity of drug in the amorphous state. Ternary SDDs containing drug, polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary SDDs. Solution-state interactions observed in binary systems may be used in tertiary systems to improve the amorphous drug capacity and improved dissolution compared to the binary. The resultant tertiary systems are an improvement over binary drug polymer systems.

Este estudio evaluó las interacciones específicas entre el fármaco y los polímeros en dispersiones amorfas secadas por pulverización (SDD). Se evaluaron cuatro fármacos de clase II del Sistema de Clasificación Biofarmacéutica (BCS). Los SDD binarios y ternarios se fabricaron con polímeros convencionales y arabinogalactano. Los parámetros de interacción específicos entre el fármaco y el polímero se determinaron utilizando cálculos teóricos y datos de DSC. Se utilizaron métodos analíticos para evaluar las interacciones del estado sólido y de la solución. El contenido amorfo máximo para cada formulación se calculó usando DSC. Se calcularon los parámetros de interacción específicos de Flory-Huggins. Los parámetros específicos negativos se asociaron con interacciones en estado sólido y una capacidad mejorada del fármaco en el estado amorfo. Los SDD ternarios que contienen fármaco, polímero y arabinogalactano mostraron enlaces de hidrógeno similares a los observados con los SDD binarios. Las interacciones de estado de solución observadas en sistemas binarios pueden usarse en sistemas terciarios para mejorar la capacidad del fármaco amorfo y mejorar la disolución en comparación con el binario. Los sistemas terciarios resultantes son una mejora con respecto a los sistemas de polímeros de fármacos binarios.

Vendor qualification: Utilization of solid state characterization “Toolbox” to assess material variability for active pharmaceutical ingredient

One of the credos for a successful product development, early clinical trial supplies, achieving full-scalemanufacturability and speed to the market is the vendor qualification. The focus of this paper is to employ a systematicapproach to qualify different active pharmaceutical ingredient (API) suppliers. In this context, API sourced from twodifferent vendors used in product development, where prototype formulations manufactured with identical componentsand specifications demonstrated significant variations in drug product performance attributable to vendor-to-vendorvariability. Prototype prepared using API (Vendor 1) showed disintegration of tablets in 4.5 minutes which compliedwith in-house specifications, whereas it was >15 minutes for the prototype prepared from API (Vendor 2). In orderto understand these differences, a vast array of solid state techniques were employed to compare the critical materialattributes of API (GDCS1902) from two different Vendors. Furthermore, these tools were orthogonally applied tounderstand whether API from two Vendors demonstrated any process-induced transformations, such as processinduced polymorphism, process-induced crystal disorder, and process-induced fragmentation. The results of thesemeasurements indicated the presence of fine particles of varied morphology with API (Vendor 1), while API (Vendor2) showed more medium-sized uniform particles. Formulation process modification to induce API fragmentation insitu was carried out for the API from Vendor 2. This modification produced desired granule properties which were thensubjected to drug performance tests and was found to match the specification. This study demonstrates the importanceof understanding the critical material attributes to match the final product performance when multiple vendors wereselected.

Irbesartan desmotropes:Solid-state characterization, thermodynamic study and dissolution properties / 药物分析学报

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible struc-tures, 1H-and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98％relative humidity (RH), 25 ?C and 40 ?C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 ?C and 98％RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.

Polimorfismo na produção de medicamentos / Polymorphism in the manufacture of medicines

O polimorfismo pode ocasionar desvios de qualidade durante o processo produtivo e influenciar o desempenho dos medicamentos. Por isso, o entendimento do fenômeno e suas implicações abre um campo amplo de possibilidades a serem exploradas na área farmacêutica, incluindo o surgimento de novos paradigmas e ferramentas na garantia da qualidade de medicamentos. Este trabalho apresenta uma introdução aos aspectos básicos do fenômeno do polimorfismo e suas implicações na produção e controle de medicamentos, com ênfase no polimorfismo dos fármacos.

Polymorphism can cause quality deviations during the production of medicines and can influence their effectiveness. Therefore, an understanding of this phenomenon and its implications opens a wide of possibilities to be explored in the pharmaceutical , including the emergence of new paradigms and tools for the quality assurance of medicines. This paper presents an introduction to basic aspects of the polymorphism phenomenon and its implications for the production and control of medicines, with emphasis on drug polymorphs.