Elena Simone

Tailoring crystal shape and polymorphism using combinations of solvents and a structurally related additive

Controlling polymorphism is one of the most difficult challenges for the pharmaceutical industry. Polymorphs of the same compound can have very different properties that might affect the quality of the final drug. Many studies have focused on trying to determine robust methods to produce specific polymorphs that exhibit the desired characteristics of the drug (solubility and rate of dissolution in particular). The choice of solvent, pH, kinetic conditions and the presence of impurities can all have very strong effects on the polymorphic outcome of cooling crystallization. In this work, the crystallization of ortho-aminobenzoic acid (OABA) in the presence of a structurally related additive (benzoic acid) will be studied using both in situ PAT tools and offline techniques. The effect on morphology, polymorphic outcome, polymorphic transformation kinetics and tendency towards agglomeration in different solvents will be studied using a large variety of instrumentation. The incorporation of benzoic acid in solid solution in the three different polymorphs of OABA will also be quantified and discussed. The results of the crystallization experiments and offline analysis will be compared and interpreted using the information on the crystal structures of the three OABA polymorphs from the Cambridge Crystallographic database.

Real-time monitoring of the mechanism of ibuprofen-cationic dextran crystanule formation using crystallization process informatics system (CryPRINS)

One step aqueous melt-crystallization and in situ granulation was utilized to produce ibuprofen-cationic dextran [diethylaminoethyl dextran (Ddex)] conjugate crystanules without the use of surfactants or organic solvents. This study investigates the mechanism of in situ granulation-induced crystanule formation using ibuprofen (Ibu) and Ddex. Laboratory scale batch aqueous crystallization system containing in situ monitoring probes for particle vision measurement (PVM), UV-vis measurement and focused beam reflectance measurements (FBRM) was adapted using pre-defined formulation and process parameters. Pure ibuprofen showed nucleation domain between 25 and 64°C, producing minicrystals with onset of melting at 76°C and enthalpy of fusion (ΔH) of 26.22kJ/mol. On the other hand Ibu-Ddex crystanules showed heterogeneous nucleation which produced spherical core-shell structure. PVM images suggest that internalization of ibuprofen in Ddex corona occurred during the melting phase (before nucleation) which inhibited crystal growth inside the Ddex corona. The remarkable decrease in ΔH of the crystanules from 26.22 to 11.96kJ/mol and the presence of broad overlapping DSC thermogram suggests formation of ibuprofen-Ddex complex and crystalline-amorphous transformation. However Raman and FTIR spectra did not show any significant chemical interaction between ibuprofen and Ddex. A significant increase in dissolution efficiency from 45 to 81% within 24h and reduced burst release provide evidence for potential application of crystanules in controlled drug delivery systems. It was evident that in situ granulation of ibuprofen inhibited the aqueous crystallization process. It was concluded that in situ granulation-aqueous crystallization technique is a novel unit operation with potential application in continuous pharmaceutical processing.

Investigation of the Evolution of Crystal Size and Shape during Temperature Cycling and in the Presence of a Polymeric Additive Using Combined Process Analytical Technologies

Crystal size and shape can be manipulated to enhance the qualities of the final product. In this work the steady-state shape and size of succinic acid crystals, with and without a polymeric additive (Pluronic P123) at 350 mL, scale is reported. The effect of the amplitude of cycles as well as the heating/cooling rates is described, and convergent cycling (direct nucleation control) is compared to static cycling. The results show that the shape of succinic acid crystals changes from plate- to diamond-like after multiple cycling steps, and that the time required for this morphology change to occur is strongly related to the type of cycling. Addition of the polymer is shown to affect both the final shape of the crystals and the time needed to reach size and shape steady-state conditions. It is shown how this phenomenon can be used to improve the design of the crystallization step in order to achieve more efficient downstream operations and, in general, to help optimize the whole manufacturing process.

A link between the ATR-UV/Vis and Raman spectra of zwitterionic solutions and the polymorphic outcome in cooling crystallization

Many substances can exist in different crystalline forms called polymorphs that have the same chemical formula but different properties such as solubility, density, melting point, stability or bioavailability. In order to guarantee the purity and quality of the final product it is very important to monitor and control the polymorphic form of the crystals during batch or continuous crystallization. Additionally, understanding the solvent effect and how the equilibrium of the different chemical species in solution influences the nucleation and transformation of different polymorphs is fundamental for better design and control of polymorphic crystallization processes. Zwitterionic compounds represent an important class of active pharmaceutical ingredients; in this study ATR-UV/Vis and Raman spectroscopy are used to investigate the relationship between the amount of zwitterions in the clear solution and the polymorphic outcome of cooling crystallizations, using anthranilic acid (OABA) as the model compound. It is shown that the shift in the UV absorbance and in the Raman signal in clear solution caused by changing the equilibrium of different species of OABA (by modifying the composition of the solvent) can be correlated with the polymorphic outcome of the crystallization. The results provide new insight on the effect of equilibrium of the ionic, zwitterionic and neutral species in solution on the polymorphic outcome of crystallization and demonstrate how UV and Raman spectroscopy can be used to control the polymorphic crystallization of zwitterionic compounds by manipulating the solvent composition.

Preventing Crystal Agglomeration of Pharmaceutical Crystals Using Temperature Cycling and a Novel Membrane Crystallization Procedure for Seed Crystal Generation

In this work, a novel membrane crystallization system was used to crystallize micro-sized seeds of piroxicam monohydrate by reverse antisolvent addition. Membrane crystallization seeds were compared with seeds produced by conventional antisolvent addition and polymorphic transformation of a fine powdered sample of piroxicam form I in water. The membrane crystallization process allowed for a consistent production of pure monohydrate crystals with narrow size distribution and without significant agglomeration. The seeds were grown in 350 g of 20:80 w/w acetone-water mixture. Different seeding loads were tested and temperature cycling was applied in order to avoid agglomeration of the growing crystals during the process. Focused beam reflectance measurement (FBRM); and particle vision and measurement (PVM) were used to monitor crystal growth; nucleation and agglomeration during the seeded experiments. Furthermore; Raman spectroscopy was used to monitor solute concentration and estimate the overall yield of the process. Membrane crystallization was proved to be the most convenient and consistent method to produce seeds of highly agglomerating compounds; which can be grown via cooling crystallization and temperature cycling.

Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays

Microcrystals of piroxicam (PRX) monohydrate with a narrow size distribution were prepared from acetone/PRX solutions by antisolvent crystallization via metallic membranes with ordered pore arrays. Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent. A complete transformation of an anhydrous form I into a monohydrate form of PRX was confirmed by Raman spectroscopy and differential scanning calorimetry. The size of the crystals was 7–34 μm and was controlled by the PRX concentration in the feed solution (15–25 g L–1), antisolvent/solvent volume ratio (5–30), and type of antisolvent (Milli-Q water or 0.1–0.5 wt % aqueous solutions of hydroxypropyl methyl cellulose (HPMC), poly(vinyl alcohol) or Pluronic P-123). The smallest crystals were obtained by injecting 25 g L–1 PRX solution through a stainless-steel membrane with a pore size of 10 μm into a 0.06 wt % HPMC solution stirred at 1500 rpm using an antisolvent/solvent ratio of 20. HPMC provided better steric stabilization of microcrystals against agglomeration than poly(vinyl alcohol) and Pluronic P-123, due to hydrogen bonding interactions with PRX and water. A continuous production of large PRX monohydrate microcrystals with a volume-weighted mean diameter above 75 μm was achieved in a continuous stirred membrane crystallizer. Rapid pouring of Milli-Q water into the feed solution resulted in a mixture of highly polydispersed prism-shaped and needle-shaped crystals.

Crystallization process monitoring and control using process analytical technology

Abstract In the past two decades, crystallization process understanding and development has been significantly improved by the use of process analytical technology methods. This chapter aims to give an overview of process analytical technology-based crystallization monitoring and control concepts. First a description of the available crystallization monitoring technologies is given, then control strategies for both batch and continuous processes are discussed. For batch crystallization processes, three feedback control methods, namely, control chart-based switching between nucleation and ripening steps, concentration or supersaturation control, automated direct nucleation control, and polymorphic feedback control are covered. Additionally, optimal solvent selection using process analytical technology as a polymorph control method is also discussed. The continuous crystallization monitoring and control related topics include automated direct nucleation control, polymorphic control, and encrustation monitoring.

Model Based Estimation of 2D Crystallization Kinetics From Concentration and CLD Measurements

Due to the fact that crystal size and shape influence relevant macroscopic properties of solid particles, the understanding and control of these quantities have increasing importance in particulate science. Crystallization, the primary crystal formation and purification process, is usually tracked real-time, in situ, by spectroscopic techniques and Focused Beam Reflectance Measurement (FBRM). This sensor can measure the chord length distribution (CLD) of a population of particles suspended in a solution. The CLD is related to both the size and shape of the particles and it is measured using a rotating infrared laser beam that emanates through the probe window inserted in the suspension. During its rotation, the beam hits the particles within the sample and is reflected back to the probe. The calculated length of laser-crystal intersection is the so-called chord length. FBRM can provide a large amount of useful information during crystallization processes, however, since the CLD is significantly different compared to the actual crystal size and shape distribution (CSD), it is normally not used for the quantification of the kinetics of crystal growth and nucleation. Usually off-line techniques (laser diffraction, microscopy, ultrasound) are exploited. In this study we develop and present a new, projection based forward 2D CSD➔CLD transformation technique. In addition, a 2D population balance model is employed to simulate the evolution of 2D CSD and solute concentration. The model equations are solved by a high resolution finite volume method, involving GPU acceleration for improved simulation time. Such model allows the use of FBRM data for the estimation of the kinetics of crystallization, without relying on off-line measurements of CSD. As model system succinic acid is used. This forms prism-like crystals in the presence of growth rate modifiers. Crystal breakage is minimized through reduced mixing rate and the kinetics of primary and secondary nucleation as well as the growth and dissolution of individual crystal facets were estimated by developing and solving a process optimization problem. The result of the parameter regression was a calibrated model, which simulates fairly the concentration and CLD variations too.