The production of crystalline powders by spray drying to improve the mechanical and flow properties of an active pharmaceutical ingredient
Citation:
MCDONAGH, ALAN FRANCIS, The production of crystalline powders by spray drying to improve the mechanical and flow properties of an active pharmaceutical ingredient, Trinity College Dublin.School of Pharmacy & Pharma. Sciences, 2020Download Item:
Abstract:
The overall aim of this research was to crystallise a drug onto the surface of an excipient (EXP) using a spray dryer in order to improve the processability of the attached active pharmaceutical ingredient (API). The project was conducted incrementally, first investigating the API and its spray drying behaviour, then the EXP both individually and as part of a co-spray dried (co-SD) mixture with the API. The resulting powders were then investigated in terms of the material?s tabletting properties. Finally, knowledge obtained from the previous investigations was applied to the heterogeneous crystallisation of the API onto the surface of the EXP in order to investigate the use of the EXP as a carrier particle to improve the processability of the poorly processable API. Throughout all investigations the same API (paracetamol), EXP (α-lactose monohydrate) and solvents (ethanol/water) were used to allow for greater comparability between the various studies. To understand the effect of spray drying this drug, a series of investigations were conducted in which the material was spray dried (SD) at various spray dryer inlet temperatures (Tin) and ethanol (EtOH)/water (H2O) solvent composition (Sc) ratios due to the importance of both these parameters to the evaporative crystallisation process. Using semi-empirical relationships to characterise droplets, the spray drying process was described for each system in terms of the drying behaviour of the atomised droplet within the spray drying system. Through parallel solid-state characterisation, correlations were made between the spray drying parameters chosen and the particle size of the SD materials. Both the spray drying Tin and Sc had an influence on the size and shape of the PAR with larger materials being produced at higher Tin and higher H2O concentrations in the inlet feed. This was attributed to the change in drying behaviour of the atomised droplets, characterised by the dimensionless Peclet number (Pe), resulting in a reduction in material density at these spray drying parameters. The drying mechanism was then investigated through the co-spray drying of the API with LαH2O using the same spray dryer inlet temperatures and solvent compositions. PAR and LαH2O were co-SD at various Tin and Sc to investigate the effect of these parameters on the co-processing of the two components. By using a modification of the spherical crystallo-co-crystallisation method, agglomerate formation was achieved through the diffusion of components in an atomised droplet in the direction of the centre of the droplet during drying with crystalline blends of the two components obtained with varying degrees of constituent mixing. This process, presently called crystallo-co-spray drying (CCSD), produced agglomerated mixtures of the two components based on the degree of EXP solubility in the inlet feed as a result of the varying concentration of EtOH. This resulted in an increase in component mixing and was evident in differential scanning calorimetry (DSC) with a greater degree of LαH2O melting point depression seen with increasing H2O concentration in the inlet feed. Subtle variations in the second derivative Fourier transform infra-red (FTIR) spectra of the co-SD agglomerates showed changes around the hydroxyl and amide functional groups of PAR and the hydroxyl groups of the LαH2O. This interaction, and increase in constituent mixing in the co-SD agglomerates, highlighted the material as a possible candidate for direct compression and for this reason the tabletting properties of the crystalline agglomerates were investigated. With an increase in H2O concentration in the inlet feed, and subsequent increase in soluble fraction of the EXP, there was an increase in the tensile strength of the resulting tablets. This increase in strength was attributed to the increase in constituent mixing of the two components and reduction in material density. With such a reduction in density came the largest reduction in material porosity as the compression pressure increased. This improvement in compressibility resulted in more particle rearrangement under compression and therefore an increase in interparticle bonding. The processability of the materials were further investigated using friability and disintegration testing. The agglomerate produced at the highest H2O concentration used, passed the criteria set by the United States Pharmacopoeia for friability testing over three compression pressures and the criteria for disintegration at the lowest compression pressure used. This agglomerate was the best performing material of all the agglomerates investigated. The strength of the compacts produced at higher EXP soluble fractions was evident in compactibility plots with agglomerates produced using this Sc having the highest tensile strength with respect to tablet porosity levels. Traditionally, with an increase in PAR concentration within a mixture, the tabletting performance of the overall material would be negatively impacted. However, when the API was co-SD with an EXP at high EXP soluble fraction, the strength of the overall material increased. This was particularly interesting in that the concentration of the API was higher (60% w/w) than what was initially expected (50% w/w) in the co-SD agglomerate due to LαH2O deposition on the inner walls of the spray dryer glassware, evident in dissolution results. The behaviour of PAR and LαH2O both individually and as part of a co-SD mixture played a key role in optimising the crystallisation of the API onto the surface of the EXP. The concentration ratio of PAR to LαH2O also played a role with more homogeneously and heterogeneously crystallised PAR, evident at higher concentrations. The spray drying process was the cause of these structures formation as PAR crystallised onto the surface of LαH2O through the slow evaporation of EtOH produced semi-prism shaped crystals after crystallisation. To greater understand the co-spray drying process, a spray dryer parameter analysis (SDPA) was conducted to investigate the effect of the spray dryer Tin, inlet feed rate, aspirator rate, dispersion force and API to EXP concentration on the quantity of homogeneous PAR that formed, the size of these homogeneous agglomerates, the quantity of heterogeneous PAR that formed, the size of these heterogeneous agglomerates, the quantity of heterogeneous surface coating and the quantity of heterogeneous agglomerated structures. With the aim being to maximise the amount of PAR on the surface of the LαH2O and minimise the amount that crystallised homogeneously, a low spray dryer Tin, high inlet feed rate, high aspirator rate, high atomising gas flow rate and low API-EXP concentration ratio (5% w/w) was chosen to be optimal. The next step was to optimise the surface of the LαH2O for PAR attachment and to make API-EXP differentiation easier in SEM imaging. To do this, LαH2O was recrystallised using Carbopol gel. The resulting crystals were defined with clear, smooth surfaces ideal for PAR attachment. To optimise this process further, a design of experiment (DOE) was conducted to maximise the yield of crystals in the size fraction 53 < ?m < 106. This DOE indicated that a low Carbopol concentration, high LαH2O concentration and low crystallisation time maximised the yield of crystals in this size fraction with respect to the weight of LαH2O initially added to the crystallisation vessel. The EXP was co-SD with the API at the optimum conditions for heterogeneous growth and the dried powder was sieved with a brush to remove any chipped LαH2O particles or any homogeneously crystallised PAR. The resulting powder was then characterised through solid-state analysis, tabletability and flowability studies. Dynamic vapour sorption (DVS) analysis indicated that a crystalline material was produced, further confirmed using powder X-ray diffraction (PXRD). DVS also showed that PAR on the surface of the LαH2O hindered H2O desorption at the end of the first cycle. Second derivative FTIR spectra of the co-SD agglomerate showed slight changes around hydroxyl groups of LαH2O and the amide group of PAR. There was a shift in the peak corresponding to the hydroxyl group of PAR to a higher wavenumber indicating the possible formation of a hydrogen bond. Tabletting studies showed tablets produced using PAR on its own had a higher tensile strength at lower compression pressures than the materials containing LαH2O as a result of the API?s low density and the large size of the EXP. This changed however as the compression pressure increased where elastic recovery had a larger influence on the API, and the EXP began to fracture. All materials containing LαH2O behaved similarly showing that the addition of PAR had no effect on the tabletting properties of the material. With PAR not hindering tablet formation, the flowability was then investigated to understand the influence of the API. Various methods of powder flow characterisation were employed using dynamic and shear tests from a powder rheometer, and by characterising the powder?s density. What was found was that the PAR processed on its own was very cohesive and did not flow well. However, when crystallised onto the surface of the substrate, the excipients favourable flow properties masked this hinderance to flow. In the case of measuring the material?s flow function (FF), the co-SD mixture had the best flow properties of all the materials testing as a result of the rounding effect of the heterogeneously crystallised PAR which reduced the mechanical interlocking between the LαH2O crystals. In conclusion, by understanding the spray drying behaviour of an API, and an EXP through solid-state characterisation. As well as their co-spray drying and the role of the spray drying parameters and surface functional group complementarity, the API can be reliably crystallised onto the surface of the EXP using a spray dryer, if the surface morphology and size of the EXP is tailored in the direction of promoting the process. Such a method is capable of producing an agglomerated mixture of the two components, with the bulk characteristics of improved flowability and tabletting properties, over the API processed independently of the EXP offering the API improved characteristics for die-filling and direct compression.
Sponsor
Grant Number
Irish Research Council (IRC)
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:MCDONAA4Description:
APPROVED
Author: MCDONAGH, ALAN FRANCIS
Advisor:
Tajber, LidiaPublisher:
Trinity College Dublin. School of Pharmacy & Pharma. Sciences. Discipline of PharmacyType of material:
ThesisCollections
Availability:
Full text availableMetadata
Show full item recordLicences: