Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 ≤ X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 ≤ X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 ≤ X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (χ) were determined for the two systems (χ = -1.8 for SDM, χ = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co-milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems.

Dry powder inhaler (DPI) products have traditionally comprised a simple formulation of micronised drug mixed with a carrier excipient, typically lactose monohydrate. The presence of the carrier is aimed at overcoming issues of poor flowability and dispersibility, associated with the cohesive nature of small, micronised active pharmaceutical ingredient (API) particles. Both the powder blend and the DPI device must be carefully designed so as to ensure detachment of the micronised drug from the carrier excipient on inhalation. Over the last two decades there has been a significant body of research undertaken on the design of carrier-free formulations for DPI products. Many of these formulations are based on sophisticated particle engineering techniques; a common aim in formulation design of carrier-free products being to reduce the intrinsic cohesion of the particles, while maximising dispersion and delivery from the inhaler. In tandem with the development of alternative formulations has been the development of devices designed to ensure the efficient delivery and dispersion of carrier-free powder on inhalation. In this review we examine approaches to both the powder formulation and inhaler design for carrier-free DPI products.

Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100C==, Carbopol and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully XCray amorphous following exposure to 90% RH at 25 oC, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug.Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCASC") and HPMCASCMG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability and antimicrobial activity.

Alum is the principal vaccine adjuvant for clinical applications but it is a poor inducer of cellular immunity and is not an optimal adjuvant for vaccines where Th1 responses are required for protection. The mechanism underlying the inefficiency of alum in promoting Th1 responses is not fully understood. We show that aluminium hydroxide, aluminium phosphate, and calcium phosphate adjuvants inhibit the secretion of the Th1 polarizing cytokine, IL-12 by dendritic cells (DCs). Alum selectively inhibited DC expression of the IL-12p35 subunit and the inhibitory effect results from adjuvantinduced PI3 kinase signaling. To develop a more effective adjuvant for promoting cellmediated immunity, we investigated alternative particulates and found that in contrast to alum, the cationic polysaccharide chitosan did not inhibit IL-12 secretion. A combination of chitosan and the TLR9 agonist CpG activated the NLRP3 inflammasome and enhanced secretion of IL-12 and the other key Th1 and Th17-cell polarizing cytokines. When used as an adjuvant, CpG-chitosan induced NLRP3-dependent antigen-specific Th1 and Th17 responses. A combination of alum and CpG also enhanced Th1 and Th17 responses but was less effective than CpG-chitosan. Therefore, chitosan is an attractive alternative to alum in adjuvants for vaccines where potent cell-mediated immunity is required. Keywords IntroductionThere is a pressing need for novel vaccine adjuvants that are effective in safely promoting cellular immunity for diseases including Correspondence: Dr. Ed C. Lavelle e-mail: lavellee@tcd.ie tuberculosis (TB), malaria, and HIV [1]. Alum is the most widely used adjuvant for clinical applications and has been used in multiple vaccines for the past 80 years. However, while alum is a very effective adjuvant for promoting humoral immunity and Th2 type * These authors contributed equally to this work. The inefficiency of alum and related adjuvants as activators of Th1 responses suggests that additional signals are required for particulates to effectively promote cell-mediated immunity. Indeed, it has been shown that combining alum with IL-12 enhanced IgG2a antibody and Th1 responses to an HIV antigen compared with alum alone [19]. Combinations of emulsions, alum, or microparticles with PAMPs, particularly TLR4 agonists, are being used to amplify adaptive immunity [20][21][22] and are under active investigation for inclusion in a new generation of vaccines. To advance the development of this new generation of vaccine adjuvants with greater potency, it is essential to optimize both the particulate and immunostimulatory adjuvants to produce systems that act in synergy to drive appropriate T-cell responses. A recent report suggests that co-administration of CpG with alum results in a suppression of Th1-dependent antigen-specific IgG2a responses compared with administration of CpG alone [23]. We demonstrate that alum strongly inhibits the secretion of TLR agonistinduced IL-12 by DCs and these inhibitory effects are dependent on PI3 kinase signaling. In contrast to a...

Multi-ionisable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallise ciprofloxacin, a poorly water soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ~215 and ~228 °C, while the glass transition temperatures of CHS-III and CS-III were ~101 and ~79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve non-congruently leading to high and sustainable drug solution concentrations in water at 25 and 37 ºC, with the ciprofloxacin concentration of 58.8±1.18 mg/ml after 1 hour of the experiment at 37 ºC. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically-relevant properties, including molecular, solid state and solubility characteristics.

In 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.

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Low physical stability is the main reason limiting the widespread use of amorphous pharmaceuticals. One approach to overcome this problem is to mix these drugs with various excipients. In this study coamorphous drug-drug compositions of different molar ratios of ezetimib and indapamid (i.e., EZB 10:1 IDP, EZB 5:1 IDP, EZB 2:1 IDP, EZB 1:1 IDP and EZB 1:2 IDP) were prepared and investigated using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), and X-ray diffraction (XRD). Our studies have shown that the easily recrystallizing ezetimib drug can be significantly stabilized in its amorphous form by using even a small amount of indapamid (8.8 wt %). DSC experiments indicate that the glass transition temperature (Tg) of the tested mixtures changes with the drug concentration in accordance with the Gordon-Taylor equation. We also investigated the effect of indapamid on the molecular dynamics of the ezetimib. As a result it was found that, with increasing indapamid content, the molecular mobility of the binary drug-drug system is slowed down. Finally, using the XRD technique we examined the long-term physical stability of the investigated binary systems stored at room temperature. These measurements prove that low-molecular-weight compounds are able to significantly improve the physical stability of amorphous APIs.