Experimental Elucidation of Templated Crystallization and Secondary Processing of Peptides.

The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates' positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising in the presence of silica with pore sizes of 6 nm and 10 nm, respectively. The diglycine induction time had a direct relationship with the silica pore size. The stable form (α-form) of diglycine was crystallised in the presence of porous silica, with the diglycine crystals obtained associated with the silica particles. Further, we studied the mechanical properties of diglycine tablets for their tabletability, compactability, and compressibility. The mechanical properties of the diglycine tablets were similar to those of pure MCC, even with the presence of diglycine crystals in the tablets. The diffusion studies of the tablets using the dialysis membrane presented an extended release of diglycine through the dialysis membrane, confirming that the peptide crystal can be used for oral formulation. Hence, the crystallization of peptides preserved their mechanical and pharmacological properties. More data on different peptides can help us produce oral formulation peptides faster than usual.

Relating Crystal Structure to Surface Properties: A Study on Quercetin Solid Forms.

The surface energy and surface chemistry of a crystal are of great importance when designing particles for a specific application, as these will impact both downstream manufacturing processes as well as final product quality. In this work, the surface properties of two different quercetin solvates (quercetin dihydrate and quercetin DMSO solvate) were studied using molecular (synthonic) modeling and experimental techniques, including inverse gas chromatography (IGC) and contact angle measurements, to establish a relationship between crystal structure and surface properties. The attachment energy model was used to predict morphologies and calculate surface properties through the study of their growth synthons. The modeling results confirmed the surface chemistry anisotropy for the two forms. For quercetin dihydrate, the {010} facets were found to grow mainly by nonpolar offset quercetin-quercetin stacking interactions, thus being hydrophobic, while the {100} facets were expected to be hydrophilic, growing by a polar quercetin-water hydrogen bond. For QDMSO, the dominant facet {002} grows by a strong polar quercetin-quercetin hydrogen bonding interaction, while the second most dominant facet {011} grows by nonpolar π-π stacking interactions. Water contact angle measurements and IGC confirmed a greater overall surface hydrophilicity for QDMSO compared to QDH and demonstrated surface energy heterogeneity for both structures. This work shows how synthonic modeling can help in the prediction of the surface nature of crystalline particles and guide the choice of parameters that will determine the optimal crystal form and final morphology for targeted surface properties, for example, the choice of crystallization conditions, choice of solvent, or presence of additives or impurities, which can direct the crystallization of a specific crystal form or crystal shape.

Understanding flow properties of mannitol powder at a range of temperature and humidity.

Inadequate flowability of powders in industries during handling can cause many problems. For example, lack of flow from hoppers, poor tablet weight consistency, and low production rate in tableting. Many factors are known to commonly affect flow properties of powders, such as temperature, humidity and conditioning duration. In this paper, flow properties of a mannitol powder, which was conditioned between 24 and 72 h at various high relative humidities and temperature, were measured using a shear tester. A statistical model was developed to investigate the relative importance of these variables on the mannitol flow properties. The developed model showed all independent variables are significant in estimating bulk cohesion. Two separate approaches were used to evaluate inter-particle forces in the bulk, and how these changed with environmental conditions. First, inter-particle forces were inferred from the measured bulk properties using the Rumpf model approach. Secondly, inter-particle forces were predicted based on a model of moisture present on the particle surface using a combination of Kelvin model with the Laplace-Young (KLY) equation. The second approach also involved a new method to measure surface energy of mannitol powder based on measurements using Finite Dilution Inverse Gas Chromatography (FD-IGC). The surface energies of the mannitol powder were measured at high temperature (35 °C) and at different range of relative humidities. In spite of the fundamentally different approaches to the two ways of inferring inter-particles forces, these forces came out within less than 1.5:1 in magnitude. The Rumpf approach from bulk behaviour data obviously reflected the measured change in behaviour with humidity in particular, but this was not predicted from the KLY approach, however the likely reasons for this are postulated and recommendations for improvement are made.

Influence of interparticle structuring on the surface energetics of a binary powder system.

The structuring of component particles in binary compositions affects the solid-solid interfacial properties. This work reports the effect of interparticle interactions in binary powder compositions of D-Mannitol and glass beads through the heterogeneity data obtained from Finite Dilution Inverse Gas Chromatography (FD-IGC). Three different scenarios viz. structured, random and segregated systems of the binary powder composition were considered for the analysis in the IGC column. Binary mixtures with large size disparity between the components produced structured mixtures exhibiting a guest-host type of interactions and energetic homogeneity irrespective of the energetics of the finer component. Random and segregated systems revealed a heterogeneous trend in the data indicating preferential probing of the active sites of the composition, particularly at the lower probe coverages. The results demonstrate that in the multicomponent binary systems the surface energetics is influenced by the solid-solid interfaces and structuring of the component particles within the mix i.e., the surface energy analysis could reveal a mixing behavior in powders. Furthermore, an adsorption energy distribution model based on Boltzmann statistics and simulation fitting approach was employed to deconvolute the distribution of the changing energy landscape of the binary mixtures.

Influences of Crystal Anisotropy in Pharmaceutical Process Development.

Crystalline materials are of crucial importance to the pharmaceutical industry, as a large number of APIs are formulated in crystalline form, occasionally in the presence of crystalline excipients. Owing to their multifaceted character, crystals were found to have strongly anisotropic properties. In fact, anisotropic properties were found to be quite important for a number of processes including milling, granulation and tableting. An understanding of crystal anisotropy and an ability to control and predict crystal anisotropy are mostly subjects of interest for researchers. A number of studies dealing with the aforementioned phenomena are grounded on over-simplistic assumptions, neglecting key attributes of crystalline materials, most importantly the anisotropic nature of a number of their properties. Moreover, concepts such as the influence of interfacial phenomena in the behaviour of crystalline materials during their growth and in vivo, are still poorly understood. The review aims to address concepts from a molecular perspective, focusing on crystal growth and dissolution. It begins with a brief outline of fundamental concepts of intermolecular and interfacial phenomena. The second part discusses their relevance to the field of pharmaceutical crystal growth and dissolution. Particular emphasis is given to works dealing with mechanistic understandings of the influence of solvents and additives on crystal habit. Furthermore, comments and perspectives, highlighting future directions for the implementation of fundamental concepts of interfacial phenomena in the rational understanding of crystal growth and dissolution processes, have been provided.

Influence of particle properties on powder bulk behaviour and processability.

Understanding interparticle interactions in powder systems is crucial to pharmaceutical powder processing. Nevertheless, there remains a great challenge in identifying the key factors affecting interparticle interactions. Factors affecting interparticle interactions can be classified in three different broad categories: powder properties, environmental conditions, and powder processing methods and parameters. Although, each of these three categories listed is known to affect interparticle interactions, the challenge remains in developing a mechanistic understanding on how combination of these three categories affect interparticle interactions. This review focuses on the recent advances on understanding the effect of powder properties, particularly particle properties, its effect on interparticle interactions and ultimately on powder bulk behaviour. Furthermore, this review also highlights how particle properties are affected by the particle processing route and parameters. Recent advances in developing a particle processing route to prepare particles with desired properties allowing desired interparticle interaction to deliver favoured powder bulk behaviour are also discussed. Perspectives for the development of potential particle processing approaches to control interparticle interaction are presented.

Fine powder flow under humid environmental conditions from the perspective of surface energy.

The influence of humidity on surface energetics and flow behavior of fine pharmaceutical powders was investigated. Amorphous and crystalline fine powders with hydrophilic (Corn starch and Avicel PH105) and hydrophobic (ibuprofen) nature were considered for this study. The surface energy was determined using surface energy analyzer and flow behavior was measured in terms of unconfined yield stress (UYS) using a shear tester. The study showed that unlike hydrophobic ibuprofen powder, surface energy and flow of hydrophilic excipient powders were affected by relative humidity (RH). The Lifshitz-van der Waals dispersive (γ(LW)) component of surface energy barely changed with varying RH for all pharmaceutical powders. For hydrophilic excipients, the specific component of surface energy (γ(SP)) was found to increase with increasing RH. Furthermore, for these excipients, flow deterioration at elevated RH was observed due to increased capillary bridge formation. Detailed analysis showed that γ(SP) component of surface energy can be an effective indicator for flow behavior of fine powders under varying humid conditions. The present study also brought out the existence of different regimes of probable interparticle forces which dictate the bulk flow behavior of fine hydrophilic powder under humid conditions.

Influence of surface modification on wettability and surface energy characteristics of pharmaceutical excipient powders.

Influence of surface modification on wettability and surface energy characteristics of three micron size pharmaceutical excipient powders was studied using hydrophilic and hydrophobic grades of nano-silica. The wetting behavior assessed from contact angle measurements using sessile drop and liquid penetration (Washburn) methods revealed that both techniques showed similar wettability characteristics for all powders depending on the hydrophilic or hydrophobic nature of nano-coating achieved. The polar (γs(p)) and dispersive (γs(d)) components of surface energies determined using extended Fowke's equation with contact angle data from sessile drop method and inverse gas chromatography (IGC) at infinite dilution suggested a general trend of decrease in γs(d) for all the surface modified powders due to passivation of most active sites on the surface. However, depending on the nature of the functional groups present in nano-silica, γs(p) was found to be either higher or lower for hydrophilic or hydrophobic coating respectively. Results show that wettability increases with increasing γs(p). Both the techniques of surface energy determination provided comparable and similar trends in γs(p) and γs(d) components of surface energies for all excipients. The study also successfully demonstrated that surface wettability and energetics of powders can be modified by varying the level of surface coating.