Towards real-time understanding of processes in pharmaceutical powder technology

There is a need for better understanding of the processes and new ideas to develop traditional pharmaceutical powder manufacturing procedures. Process analytical technology (PAT) has been developed to improve understanding of the processes and establish methods to monitor and control processes. The interest is in maintaining and even improving the whole manufacturing process and the final products at real-time. Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. New methods are craved for to increase the quality and safety of the final products faster and more efficiently than ever before. The real-time process monitoring demands tools, which enable fast and noninvasive measurements with sufficient accuracy. Traditional quality control methods have been laborious and time consuming and they are performed off line i.e. the analysis has been removed from process area. Vibrational spectroscopic methods are responding this challenge and their utilisation have increased a lot during the past few years. In addition, other methods such as colour analysis can be utilised in noninvasive real-time process monitoring. In this study three pharmaceutical processes were investigated: drying, mixing and tabletting. In addition tablet properties were evaluated. Real-time monitoring was performed with NIR and Raman spectroscopies, colour analysis, particle size analysis and compression data during tabletting was evaluated using mathematical modelling. These methods were suitable for real-time monitoring of pharmaceutical unit operations and increase the knowledge of the critical parameters in the processes and the phenomena occurring during operations. They can improve our process understanding and therefore, finally, enhance the quality of final products.Lääketeollisuuden tavoitteena on tehostaa toimintojaan tinkimättä lääkkeiden turvallisuudesta. Jauheteknologian saralla on otettu käyttöön uusia mittausmenetelmiä, joiden avulla voidaan seurata prosesseja reaaliaikaisesti. Tällaisia menetelmiä ovat muun muassa spektroskopiset menetelmät, jotka ovat nopeita, tarkkoja, eivätkä häiritse tutkittavaa prosessia millään tavoin. Spektrokopisilla menetelmillä mitataan tutkittavasta kohteesta heijastuvaa säteilyä, jonka voimakkuudesta voidaan päätellä muun muassa kohteen kemiallinen koostumus. Prosesseja voidaan seurata myös muilla menetelmillä, esimerkiksi värianalyysin avulla. Tässä väitöstyötutkimuksessa seurattiin kolmea farmasian teknologian prosessia: kuivausta, sekoitusta ja tabletointia. Kuivaustutkimuksessa käytettiin värillisiä lämpöindikaattoriaineita, jotka vaihtavat väriään lämpötilan muuttuessa. Indikaattoriaineiden avulla tutkittiin, kuinka lämpö etenee kuivauskammiossa ja missä ovat kriittiset kohdat lämpöherkkien lääkeaineiden hajoamisen kannalta. Jauheiden sekoitusta tutkittiin puolestaan sekoittamalla lääke- ja apuainetta keskenään eri nopeuksilla. Massojen sekoittumisaste mitattiin lähi-infrapunaspektroskopialla suoraan sekoitusastiasta. Lisäksi väitöskirjassa esitellään, kuinka tabletointiprosessia voi seurata reaaliajassa paininten voimatietojen perusteella. Tabletointitutkimuksessa selvitettiin, kuinka erilaiset rakeiden ominaisuudet vaikuttavat, siihen minkälaisia tabletteja syntyy rakeita puristettaessa. Tabletoinnin kannalta olisi hyvä, jos rakeet olisivat keskenään mahdollisimman tasa-aineisia, jottei syntyisi vaihtelua syntyvien tablettien ominaisuuksiin, kuten lääkeainepitoisuuteen. Väitöskirjassa tutkittiin myös tablettien murtolujuutta Raman spektroskopian avulla. Perinteisesti murtolujuutta eli sitä kuinka helposti tabletti hajoaa, on tutkittu mittaamalla voima, joka tarvitaan murtamaan tabletti. Tämä menetelmä nimensä mukaisesti hajottaa tabletin. Raman spektroskopian avulla murtolujuus voidaan mitata koskematta tablettiin. Mittaus ei vahingoita tablettia millään tavoin, joten tabletti voidaan käyttää normaalisti mittauksen jälkeen. Lisäksi mittaus on niin nopea, että sillä voidaan tutkia jopa kaikki puristetut tabletit reaaliajassa. Reaaliajassa tapahtuva prosessien seuranta lisää ymmärrystämme siitä, mitä prosesseissa tapahtuu. Lisäksi voimme saada tietoa siitä, miksi mitäkin tapahtuu ja mitkä ovat prosessin kannalta tärkeitä tekijöitä. Mitä enemmän ymmärrämme, sitä nopeammin, tehokkaammin ja luotettavammin pystymme valmistamaan lääkkeitä ihmiskunnan kasvaviin tarpeisiin

Optimizing aerosolization of a high-dose L-arginine powder for pulmonary delivery

In this study a carrier-free dry powder inhalation (DPI) containing L-arginine (ARG) was developed. As such, it is proposed that ARG could be used for adjunctive treatment of cystic fibrosis and/or tuberculosis. Various processing methods were used to manufacture high-dose formulation batches consisting various amounts of ARG and excipients. The formulations were evaluated using several analytical methods to assess suitability for further investigation. Several batches had enhanced in vitro aerolization properties. Significant future challenges include the highly hygroscopic nature of unformulated ARG powder and identifying the scale of dose of ARG required to achieve the response in lungs

The Comparison of Two Challenging Low Dose APIs in a Continuous Direct Compression Process

Segregation is a common problem in batch-based direct compression (BDC) processes, especially with low-dose tablet products, as is the preparation of a homogenous mixture. The scope of the current work was to explore if a continuous direct compression (CDC) process could serve as a solution for these challenges. Furthermore, the principle of a platform formulation was demonstrated for low dose tablets. The combination of filler excipients and the API in the formulation used was suitable for direct compression, but also prone to induce segregation in BDC process. The CDC process was found to be very promising; it was shown that tablets with the desired quality parameters could be manufactured successfully with both of the APIs studied. Powder analysis indicated that the APIs display some fundamental differences in their physical properties, which was also reflected in powder mixture properties and, hence, eventually in processing. However, process parameters, especially mixer impeller speed, were not found to have any significant influence on end product quality. The study suggests that a CDC process can be a viable solution to resolve the challenges described. Moreover, manufacturing by using a universal platform formulation seems to be a feasible way for producing low-dose tablets

Single-step coprocessing of cohesive powder via mechanical dry coating for direct tablet compression

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression