Powder Compaction: Compression Properties of Cellulose Ethers

Effective development of matrix tablets requires a comprehensive understanding of different raw material attributes and their impact on process parameters. Cellulose ethers (CE) are the most commonly used pharmaceutical excipients in the fabrication of hydrophilic matrices. The innate good compression and binding properties of CE enable matrices to be prepared using economical direct compression (DC) techniques. However, DC is sensitive to raw material attributes, thus, impacting the compaction process. This article critically reviews prior knowledge on the mechanism of powder compaction and the compression properties of cellulose ethers, giving timely insight into new developments in this field

A holistic multi evidence approach to study the fragmentation behaviour of crystalline mannitol

Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties

Cellulose bilayer tablet interfaces

Imperial Users onl

Evaluating mechanical properties and tabletability of pharmaceutical powders with a novel gravitation-based high-velocity compaction method

Developing new pharmaceuticals is costly and time-consuming. New methods are always in demand for various stages of product development. Investing in the early phases of development can save a significant amount of resources in the long term. Tablet is still the most commonly used pharmaceutical dosage form. Tablets are often produced by powder compression. Powder particles fragment and deform under pressure, allowing new bonds to form between them. Modern machines can produce over one million tablets per hour. The mechanical properties of the powders have a remarkable impact on compact formation. For example, excessive elasticity in a powder mixture can lead to weak or defected tablets being produced. Therefore, the mechanical properties need to be studied. Devices known as tableting simulators have been designed to aid in developing adequate tablet formulations. These machines are useful, but they can still be quite expensive and large. The results obtained by these machines are not always universally applicable, and further interpretation is often required. In this thesis, a novel gravitation-based high-velocity compaction (G-HVC) method was developed to study the compressibility and tabletability of powders in a cost-efficient and straightforward manner. The method is based on a freely falling steel bar, which compresses the powder sample inside a custom-made die. The movement of the bar and the deformation wave of the system base were monitored by high-accuracy displacement sensors. Displacement graphs could then be derived further. All data obtained by the method was ultimately only based on the displacement data. First, microcrystalline cellulose (MCC) and starch samples were compressed to demonstrate the functionality of the method. MCC was shown to be more compressible and less elastic than starch. Apparent differences in the relative volume decrease and the compression behaviour of these two materials could be seen. Next, various materials were studied more comprehensively. Two different setups with varying pressure were in use. Lactose grades and glucose showed effective fragmentation and reached true density with both setups. MCC grades were clearly pressure-dependent and showed slower gradual deformation, indicating plastic behaviour. Compression pressure was not high enough to effectively fragment calcium phosphate. Starch showed most elasticity of all the samples. In summary, all examined materials could be successfully categorized in terms of their mechanical properties. Finally, the practical relevance of the method was shown by creating a model between the compaction energy values determined by G-HVC method and the tensile strength of tablets produced with a tableting machine. Three different formulations consisting of MCC, calcium phosphate, theophylline and HPMC were granulated utilizing a fluid bed system. There was a good correlation between compaction energy and tensile strength. In summary, the G-HVC method was proven to be a reliable and cost-efficient tool in the examination of the mechanical properties of powders. The method was also capable of producing practically relevant results. The method fits well in modern pharmaceutical research where material-sparing, straightforward and reliable methods are in demand.Uusien lääkevalmisteiden kehitys on kallista ja aikaa vievää. Uudenlaisia menetelmiä tarvitaan jatkuvasti lääkekehityksen eri vaiheisiin. Lääkekehityskaaren varhaisiin vaiheisiin panostaminen säästää merkittävästi resursseja pitkällä tähtäimellä. Tabletti on edelleen kaikista yleisimmin käytetty lääkemuoto. Tabletit valmistetaan usein jauheesta puristamalla. Jauhepartikkelit murtuvat ja muotoutuvat paineen alla, jolloin uusia sidoksia muodostuu partikkelien välille. Nykyaikaisilla tablettikoneilla voidaan valmistaa jopa yli miljoona tablettia tunnissa. Jauheiden mekaanisilla ominaisuuksilla on merkittävä rooli puristeen muodostumisessa. Esimerkiksi liika elastisuus puristettavassa seoksessa voi johtaa heikkojen tablettien muodostumiseen. Erilaisia puristussimulaattoreita on kehitetty tablettivalmisteiden formuloinnin avuksi. Nämä laitteet ovat hyödyllisiä, mutta ne ovat edelleen melko kalliita ja suurikokoisia. Lisäksi näillä laitteilla saadut tutkimustulokset ovat usein vaihtelevia riippuen käytössä olleesta metodista. Tässä väitöskirjatyössä kehitettiin uudenlainen gravitaatioon perustuva nopean puristamisen menetelmä (gravitation-based high-velocity compaction method, G-HVC). Menetelmän tarkoituksena oli tutkia jauheiden puristuvuutta ja tabletoitavuutta edullisesti ja yksinkertaisesti. Menetelmä perustuu vapaasti putoavaan kappaleeseen, joka puristaa muotin sisällä olevan jauhenäytteen. Kappaleen liikettä ja laitteen pohjan deformaatioaaltoa seurattiin tarkoilla liikesensoreilla. Jauheiden mekaanisia ominaisuuksia voitiin arvioida saadun liikedatan perusteella. Työosion ensimmäisessä osassa menetelmän toimivuus osoitettiin mikrokiteistä selluloosaa ja tärkkelystä puristamalla. Mikrokiteinen selluloosa oli paremmin puristuva ja vähemmän elastinen kuin tärkkelys. Näytteiden välillä oli selkeitä eroja suhteellisen tilavuuden pienenemisessä ja puristuskäyttäytymisessä. Työosion toisessa osassa useita näytteitä tutkittiin kahdella erilaisella asetelmalla, joissa oli eroja muun muassa paineen suhteen. Tutkitut laktoosilaadut ja glukoosi murtuivat hyvin puristettaessa. Mikrokiteiset selluloosanäytteet olivat selkeästi riippuvaisia käytetystä paineesta ja osoittivat plastista puristumiskäyttäytymistä. Korkean myötöpaineen omaavat kalsiumfosfaattipartikkelit eivät murtuneet käytetyillä paineilla. Tärkkelys oli tutkituista aineista kaikkein elastisin. Työosion viimeisessä osiossa menetelmän käytännöllisyys osoitettiin vertaamalla näytteistä saatuja puristusenergia-arvoja tablettikoneella valmistettujen tablettien vetolujuuksiin. Tutkimuksessa käytettiin kolmea erilaista jauheseoskoostumusta, jotka sisälsivät mikrokiteistä selluloosaa, kalsiumfosfaattia, teofylliiniä ja hydroksipropyylimetyyliselluloosaa. G-HVC-menetelmällä saaduilla puristusenergia-arvoilla oli selvä korrelaatio tablettikoneilla saatujen puristeiden vetolujuuden kanssa. Tässä väitöskirjatyössä osoitettiin, että kehitetty G-HVC-menetelmä oli luotettava ja kustannustehokas keino tutkia farmaseuttisten jauheiden puristusominaisuuksia. Tutkittu menetelmä on yksinkertainen, edullinen ja pienen näytekoon vuoksi lähtöaineita säästävä. Täten se sopii hyvin nykyaikaiseen lääkekehitystyöhön

Release kinetics, compaction and electrostatic properties of hydrophilic matrices

This thesis illustrates the behaviour of cellulose ethers during powder processing, compaction and drug release, as these are frequently employed in the fabrication of compressed hydrophilic matrices. The handling operations can give rise to the electrification of powder particles, which can affect the end product‘s quality. Controlling the parameters which can dictate the quality of compressed matrices is an ambition inherent in the development of pharmaceutical formulations. Thus, the aims and objectives of this thesis were to firstly study the electrostatic, surface adhesion, dissolution and compaction properties of plain polymers and model drugs. Secondly, binary mixtures of fixed drug to polymer ratios were made in order to investigate the effect of polymer concentration and physico-chemical attributes (particle size, chemistry and viscosity) on the tribo-electric charging, surface adhesion (SA), swelling, erosion, drug release kinetics and compaction properties of model drugs. It can be discerned that the both drugs charged negatively, whereas the methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) particles charged positively. The physico-chemical properties associated with MC and HPMC, such as particle size, chemical heterogeneity and molecular size of cellulose ethers all have a significant effect on charging and adhesion behaviour of plain MC and HPMC particles. Moreover, the concentration, particle size, chemical heterogeneity and molecular size of MC/HPMC all significantly affect the charging and SA propensity of the model drugs studied. The swelling and dissolution results confirm that the extent and rate of swelling, swelling exponent, dissolution rate and drug release kinetic parameters were affected by physico-chemical attributes (concentration, particle size, substitution and viscosity) of MC/HPMC and drug solubility. The mechanism of swelling and drug release was found to be anomalous. However, it inclined towards more diffusion-oriented swelling/drug release with higher MC/HPMC levels, viscosity, Hpo/Meo substitution ratios, drug solubility but smaller MC/MC particle size. The matrix erosion results obtained from newly developed phenol-sulphuric acid assay (PSA) method confirmed that the solubility of the drug, and levels of HPMC in a particular matrix tablet, significantly affect the matrix erosion rate and the results were similar to those determined using the much more labour-intensive gravimetric method. Moreover, the combination of conventional UV drug analysis technique and PSA assay can be used to simultaneously quantify the matrix erosion, polymer dissolution and drug release kinetics in a single set of experiments avoiding the need for separate studies. The compaction results confirmed that the FBP has poor compaction as compare to THP. The particle size, substitution ratios and molecular size of MC/HPMC affect the compaction and consolidation behaviour of plain MC/HPMC compacts. Furthermore, it can be noticed that the concentration and physico-chemical attributes (particle size, chemistry and molecular size) of MC/HPMC have a significant influence on the densification and consolidation process of hydrophilic matrices. In summary, the information obtained can be used in the future to develop and adopt strategies for development and further optimization of compressed hydrophilic matrices