Molecular Structure Studies of (1S,2S)-2-benzyl-2,3-dihydro-2-(1Hinden- 2-yl)-1H-inden-1-ol

The single enantiomer (1S,2S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol (2), has recently been synthesized and isolated from its corresponding diastereoisomer (1). The molecular and crystal structures of this novel compound have been fully analyzed. The relative and absolute configurations have been determined by using a combination of analytical tools including X-ray crystallography, X-ray Powder Diffraction (XRPD) analysis and Nuclear Magnetic Resonance (NMR) spectroscopy

An Analysis of Drug Dissolution Rates in the USP 24 Type 2 Apparatus

This paper applies boundary layer theory to the process of drug dissolution in the USP 24, Type 2 Apparatus. The mass transfer rate from the top flat surface of a compact in various positions within the device is evaluated by means of a Pohlhausen integral method

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.Peer reviewe

Solid-state characterization of novel active pharmaceutical ingredients: Cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt.

The production of salt or cocrystalline forms is a common approach to alter the physicochemical properties of pharmaceutical compounds. The goal of this work was to evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemical characteristics of salbutamol forms. Novel crystals of salbutamol were produced by solvent evaporation: a cocrystal of salbutamol hemiadipate with adipic acid (salbutamol adipate, SA), salbutamol hemisuccinate tetramethanolate (SSU.MeOH), and its desolvated form (SSU). The crystalline materials obtained were characterized using thermal, X-ray, nuclear magnetic resonance, Fourier transform infrared spectroscopy, dynamic vapor sorption (DVS), and elemental analysis. The crystal forms of SA and SSU.MeOH were determined to be triclinic, (Pī), and monoclinic, (P21/n), respectively. DVS analysis confirmed that SSU and SA do not undergo hydration under increased relative humidity. Both thermal and elemental analyses confirmed the stoichiometry of the salt forms. The aqueous solubilities of SA and SSU were measured to be 82 ± 2 mg/mL (pH 4.5 ± 0.1) and 334 ± 13 mg/mL (pH 6.6 ± 0.1), respectively. Measured values corresponded well with the calculated pH solubility profiles. The intrinsic dissolution rate of cocrystallized SA was approximately four times lower than that of SSU, suggesting its use as an alternative to more rapidly dissolving salbutamol sulfate

Continuous microfluidic manufacture of cocrystals using 3D printed chips coupled with spray coating

Cocrystals have emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high risk and complex in the manufacture of solid dosage forms. Co-crystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved soubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mix-tures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the micro-fluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implement-ed when the microfluidic chip was connected in line to a fluidized bed allowing co-crystal formulation generation by mixing

An Analysis of Drug Dissolution Rates in the USP 24 Type 2 Apparatus

This paper applies boundary layer theory to the process of drug dissolution in the USP 24, Type 2 Apparatus. The mass transfer rate from the top flat surface of a compact in various positions within the device is evaluated by means of a Pohlhausen integral method

Designing fast-dissolving orodispersible films of amphotericin B for oropharyngeal candidiasis

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B's high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25° C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis

Impact of process variables on the micromeritic and physicochemical properties of spray-dried porous microparticles, part I: introduction of a new morphology classification system

YesObjectives This work investigated the impact of spray drying variables such as feedconcentration, solvent composition and the drying mode, on the micromeriticproperties of chlorothiazide sodium (CTZNa) and chlorothiazide potassium(CTZK).Methods Microparticles were prepared by spray drying and characterised usingthermal analysis, helium pycnometry, laser diffraction, specific surface area analysisand scanning electron microscopy.Key findings Microparticles produced under different process conditions pre-sented several types of morphology.To systematise the description of morphology ofmicroparticles, a novel morphology classification system was introduced. The shapeof the microparticles was described as spherical (1) or irregular (2) and the surfacewas classified as smooth (A) or crumpled (B). Three classes of morphology of micro-particles were discerned visually: class I, non-porous; classes II and III, comprisingdiffering types of porosity characteristics. The interior was categorised as solid/continuous (a), hollow (b), unknown (g) and hollow with microparticulate content(d). Nanoporous microparticles of CTZNa and CTZK, produced without recircula-tion of the drying gas, had the largest specific surface area of 72.3 and 90.2 m2/g,respectively, and presented morphology of class 1BIIIa.Conclusions Alteration of spray drying process variables, particularly solvent com-position and feed concentration can have a significant effect on the morphology ofspray dried microparticulate products. Morphology of spray dried particles may beusefully described using the morphology classification system.The Irish Research Council for Science and Engineering Technology (IRCSET), the Solid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under grant number [07/SRC/B1158] and the Irish Drug Delivery Research Network, a Strategic Research Cluster grant (07/SRC/B1154) under the National Development Plan co-funded by EU Structural Funds and Science Foundation Ireland

Comparative study of different methods for the prediction of drug-polymer solubility

YesIn this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility.The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.)

3D printed spherical mini-tablets : geometry versus composition effects in controlling dissolution from personalised solid dosage forms

Oral dosage forms are by far the most common prescription and over-the-counter pharmaceutical dosage forms used worldwide. However, many patients suffer from adverse effects caused by their use of "one-size fits all" mass produced commercially available solid dosage forms, whereby they do not receive dedicated medication or dosage adjusted to their specific needs. The development of 3D printing paves the way for personalised medicine. This work focuses on personalised therapies for hypertensive patients using nifedipine as the model drug. 3D printed full solid and channelled spherical mini-tablets with enhanced surface area (1.6-fold higher) were printed using modified PVA commercial filaments loaded by passive diffusion (PD), and Kollidon VA64 (KVA) and ethylcellulose (EC) based filaments prepared by hot-melt extrusion (HME). Drug loading ranged from 3.7% to 60% based on the employed technique, with a 13-fold higher drug loading achieved with the HME compared to PD. Composition was found to have a more significant impact on drug dissolution than geometry and surface area. Both KVA and EC-based formulations exhibited a biphasic zero-order drug-release profile. Physicochemical characterization revealed that nifedipine was in the amorphous form in the KVA-based end-products which led to a greater dissolution control over a 24 h period compared to the EC-based formulations that exhibited low levels of crystallinity by PXRD. The proposed 3D printed spherical mini-tablets provide a versatile technology for personalised solid dosage forms with high drug loading and dissolution control, easily adaptable to patient and disease needs