Advanced

Spray drying of particles intended for inhalation - Investigation of significant process variables and product characteristics, with focus on degradation and solid state properties

Mosén, Kristina LU (2003)
Abstract (Swedish)
Popular Abstract in Swedish

Spraytorkning är ett vanligt sätt att tillverka partiklar från en lösning. Genom att finfördela lösningen med hjälp av gas i ett spraymunstycke bildas miljontals små vätskedroppar, som blandas med varm torkgas i en torkkammare. Då avdunstar vätskan och fasta, torra partiklar bildas. Tekniken kan användas för att tillverka inhalationspartiklar för användning som läkemedel. Detta ställer speciella krav på processen för att partiklarna skall få lämpliga egenskaper med bibehållen aktivitet.



I den här avhandlingen har undersökts hur processen kan påverkas så att viktiga egenskaper för inhalationspartiklarna kan styras, t.ex. partikelstorlek, partikelutseende, nedbrytning och... (More)
Popular Abstract in Swedish

Spraytorkning är ett vanligt sätt att tillverka partiklar från en lösning. Genom att finfördela lösningen med hjälp av gas i ett spraymunstycke bildas miljontals små vätskedroppar, som blandas med varm torkgas i en torkkammare. Då avdunstar vätskan och fasta, torra partiklar bildas. Tekniken kan användas för att tillverka inhalationspartiklar för användning som läkemedel. Detta ställer speciella krav på processen för att partiklarna skall få lämpliga egenskaper med bibehållen aktivitet.



I den här avhandlingen har undersökts hur processen kan påverkas så att viktiga egenskaper för inhalationspartiklarna kan styras, t.ex. partikelstorlek, partikelutseende, nedbrytning och kristallinitet. Spraytorkningen har utförts både i labskala och pilotskala. Som modellsubstanser har insulin och olika sockerarter studerats: laktos, mannitol, melezitos, myo-inositol, raffinos och trehalos. För att undersöka hur kristalliniteten av partiklarna kan påverkas har även tillsats av polyetylenglykol (PEG) med olika molekylvikt studerats.



Försöken visade att processen kan styras så att partiklar i inhalerbar storlek, < 5 mm, tillverkas. Partikelstorleken kan minskas genom en sänkt fastsubstanshalt i lösningen. Likaså kan partikelstorleken minskas genom att energitillförseln ökas, dvs högt förhållande mellan gas och vätska i spraymunstycket. Generellt är partikelstorleksfördelningen av produkten relativt snäv.



Partikelutseendet beror av startmaterialet. Vid produktion av partiklar innehållande insulin erhålls partiklar som liknar skrumpna sfärer. I samtliga fall då sockerarter spraytorkas erhålls runda, släta sfärer.



Nedbrytning av insulin kan undvikas vid spraytorkning om torkningsbetingelserna styrs så att den utgående luftens temperatur hålls tillräckligt låg (max ca 120 °C). Annars ökar nedbrytningen av insulin vid ökad torktemperatur.



Mannitol och myo-inositol blir kristallina efter spraytorkning medan de andra studerade sockerarterna blir amorfa. För att erhålla en kristallin produkt bör kristallisationstemperaturen hos materialet som torkas inte överstiga den utgående gasens temperatur och kristallisationsförloppet vara tillräckligt snabbt.



Tillsats av PEG till laktos vid spraytorkning resulterar i delvis kristallin laktos. Ju lägre molekylvikt av PEG och ju högre koncentration desto mer kristallina laktos/PEG-partiklar erhålls. Detta gäller upp till en viss gräns: ca 50-60% kristallinitet med PEG 200. Orsaken till PEG:s effekt diskuteras i avhandlingen. (Less)
Abstract
The interest in spray drying for production of inhalable particles has grown considerably since the late 1980s. However, which process variables that control degradation and the solid state properties have not been subject to extensive research.



This thesis deals with how important characteristics of inhalation particles can be controlled, i.e. particle size, morphology, degradation and crystallinity. The spray drying was performed in laboratory scale and pilot plant scale. Insulin, lactose, mannitol, melezitose, myo-inositol, raffinose and trehalose were used. In addition, in one study, the effect of an additive, polyethylene glycol (PEG), on the crystallinity of a material with a high glass transition temperature (Tg... (More)
The interest in spray drying for production of inhalable particles has grown considerably since the late 1980s. However, which process variables that control degradation and the solid state properties have not been subject to extensive research.



This thesis deals with how important characteristics of inhalation particles can be controlled, i.e. particle size, morphology, degradation and crystallinity. The spray drying was performed in laboratory scale and pilot plant scale. Insulin, lactose, mannitol, melezitose, myo-inositol, raffinose and trehalose were used. In addition, in one study, the effect of an additive, polyethylene glycol (PEG), on the crystallinity of a material with a high glass transition temperature (Tg °C) (lactose) was studied.



Particles within the inhalable size range, < 5 micrometers, were produced of insulin and the carbohydrates. The particle size was shown to be decreased by decreased feed concentration, increased nozzle gas/feed flow mass ratio and decreased inlet gas temperature (insulin). The particle morphology depends on the starting material. Degradation of insulin could be avoided at mild drying conditions (outlet gas temperature below 120 °C). The degradation increased at increased inlet gas temperature and outlet gas temperature. Mannitol and myo-inositol were crystalline after spray drying while the other carbohydrates were amorphous. A comparison of the obtained crystallinities and the conditions in the spray dryer during processing (gas- and product temperatures, gas relative humidities etc.) showed that substances with a Tg below room temperature will become crystalline and those with a Tg above 100 °C amorphous. The crystallization temperature (Tc °C) must not exceed the outlet gas temperature (Tout °C) and the Tg must be about 50 °C below the Tout to obtain a crystalline product. The addition of PEG to lactose increased the crystallinity of lactose at increased PEG concentration and at decreased PEG molecular weight. PEG 200 resulted in the most crystalline samples (50-60% crystallinity of the lactose/PEG samples at a plateau level) and the mechanism for the effect of PEG is discussed in the thesis. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Buckton, Graham, The School of Pharmacy, University of London, England
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Läkemedelsteknik och relaterad teknik, Pharmaceutical and related technologies, carbohydrate, insulin, process conditions, crystallinity, degradation, particle size, spray drying, inhalation
pages
83 pages
publisher
Dept. of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-21 00 Copenhagen, Denmark,
defense location
The Danish University of Pharmaceutical Sciences, Auditorium 3, 2 Universitetsparken, Copenhagen, Denmark.
defense date
2003-04-04 15:00
external identifiers
  • other:ISRN: LUTKDH/(TKKA-1002)/1-83/(2003)
ISSN
1100-2778
ISBN
87-7834-524-3
language
English
LU publication?
yes
id
b64a0e4a-ec8d-4220-aa3b-b8b3b32c1d13 (old id 465581)
date added to LUP
2007-10-14 14:22:16
date last changed
2018-05-29 10:09:52
@phdthesis{b64a0e4a-ec8d-4220-aa3b-b8b3b32c1d13,
  abstract     = {The interest in spray drying for production of inhalable particles has grown considerably since the late 1980s. However, which process variables that control degradation and the solid state properties have not been subject to extensive research.<br/><br>
<br/><br>
This thesis deals with how important characteristics of inhalation particles can be controlled, i.e. particle size, morphology, degradation and crystallinity. The spray drying was performed in laboratory scale and pilot plant scale. Insulin, lactose, mannitol, melezitose, myo-inositol, raffinose and trehalose were used. In addition, in one study, the effect of an additive, polyethylene glycol (PEG), on the crystallinity of a material with a high glass transition temperature (Tg °C) (lactose) was studied.<br/><br>
<br/><br>
Particles within the inhalable size range, &lt; 5 micrometers, were produced of insulin and the carbohydrates. The particle size was shown to be decreased by decreased feed concentration, increased nozzle gas/feed flow mass ratio and decreased inlet gas temperature (insulin). The particle morphology depends on the starting material. Degradation of insulin could be avoided at mild drying conditions (outlet gas temperature below 120 °C). The degradation increased at increased inlet gas temperature and outlet gas temperature. Mannitol and myo-inositol were crystalline after spray drying while the other carbohydrates were amorphous. A comparison of the obtained crystallinities and the conditions in the spray dryer during processing (gas- and product temperatures, gas relative humidities etc.) showed that substances with a Tg below room temperature will become crystalline and those with a Tg above 100 °C amorphous. The crystallization temperature (Tc °C) must not exceed the outlet gas temperature (Tout °C) and the Tg must be about 50 °C below the Tout to obtain a crystalline product. The addition of PEG to lactose increased the crystallinity of lactose at increased PEG concentration and at decreased PEG molecular weight. PEG 200 resulted in the most crystalline samples (50-60% crystallinity of the lactose/PEG samples at a plateau level) and the mechanism for the effect of PEG is discussed in the thesis.},
  author       = {Mosén, Kristina},
  isbn         = {87-7834-524-3},
  issn         = {1100-2778},
  keyword      = {Läkemedelsteknik och relaterad teknik,Pharmaceutical and related technologies,carbohydrate,insulin,process conditions,crystallinity,degradation,particle size,spray drying,inhalation},
  language     = {eng},
  pages        = {83},
  publisher    = {Dept. of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-21 00 Copenhagen, Denmark,},
  school       = {Lund University},
  title        = {Spray drying of particles intended for inhalation - Investigation of significant process variables and product characteristics, with focus on degradation and solid state properties},
  year         = {2003},
}