Relevant aspects of roller compaction covering the impact of excipients, milling devices, fines and feasibility prediction [Elektronische Ressource] / presented by Jochen Farrenkopf

Jochen Farrenkopf

Sujets

• Biologie

Informations

• Publié par: ruprecht-karls-universitat_heidelberg
• Publié le: 01 janvier 2010
• Nombre de lectures: 19
• Langue: English
• Poids de l'ouvrage: 6 Mo

Extrait

Dissertation
submitted to the
Institute of Pharmacy and Molecular Biotechnology
of the Ruperto-Carola University of Heidelberg,
Germany
for the degree of
Doctor of Natural Sciences

















presented by
Jochen Farrenkopf, Pharmacist
Place of Birth: Weinheim, Germany
Oral Examination: .................................







Relevant Aspects of Roller Compaction
covering the Impact of Excipients, Milling
Devices, Fines and Feasibility Prediction





















Referees:
Prof. Dr. rer. nat. Gert Fricker
Prof. Dr. rer. nat. Ulrich Massing


Page 2 Jochen Farrenkopf Relevant Aspects of Roller Compaction covering the Impact of Excipients, Milling Devices, Fines and
Feasibility Prediction

Abstract

Roller compaction is a dry granulation technology, used to overcome unfavorable
physical properties of powders and APIs, such as poor flow, low and/or inhomogeneous
bulk density or segregation/floating of powder blends. Simplified, two rolls are
compacting powder into a ribbon of theoretically infinite length, being milled into
granules in-line. Thorough equipment design and sophisticated instrumentation allow
reproducible, continuous manufacture as well as PAT and QbD applications. Associated
with many advantageous properties, one of the major roller compaction drawbacks is
the potential for relatively high amounts of fine particles after milling of the ribbons. To
investigate their impact, a variety of blends with different amounts of fine, medium and
coarse granules fractions were prepared to simulate a practically relevant variety of
particle size distributions. As shown for the single particle size fractions, the flow
properties of the blends strongly suffered from high presence of fines < 0.1 mm.
However, the results were better than for the unprocessed primary particles, and there
was further improvement with the medium fraction and the blends with the coarse
particles. It could be shown experimentally that the tablets tensile strength significantly
suffers from the presence of roller compacted fines, valid for blends with 15% of fines,
even more with 30% being present. A major reason can be expected in the changed
particles shape and therefore decreased ability of the pre-densified fines to flow and
align while filling the dies and during the compression phase. This alignment effect is
surprisingly over-compensated for higher amounts of fines, as the tablets tensile
strength increases for blends with 45% and 60% fines presence: now the high number
of particles and their large surface area appears to be predominant – despite the poor
flow. The best tensile strength data derived from the medium fraction 0.1 - 1.0 mm: the
wide variety of smaller and larger particles with good flow properties easily aligns during
filling and compression phase. For the coarse particles 1.0 - 1.25 mm, their limited
specific surface area and therefore reduced ability to establish interparticular bindings
has minor negative impact on the blends compressibility.
As described above, the milling step is of vital importance for the ribbons processability.
As a consequence, several milling devices (Quadro Comil 197, Frewitt mill GLA_ORV,
Gerteis granulator with standard and new sieve housing) were assessed, as well as
their settings (different sieve screen sizes, sieve types, rotor types, rotor speeds,
rotor/sieve distances, and sensible combinations thereof). The evaluation is mainly
based on the presence of resulting fine particles. Also material throughput, ease and
reproducibility of set-up and number of critical process parameters were considered.
The integrated Gerteis granulator with newly modified sieve housing delivered the best
performance, whereas for smaller ribbons quantities also the independently driven
Frewitt mill GLA_ORV prove to be a viable option.
For formulation optimization purposes, five dry binders (PEG 1500 and 4000, PVP K30,
PVP/VA copolymer, HPC) were added in low amounts to the standard formulation
(MCC as major excipient for roller compaction applications; Mg st added as lubricant).
Jochen Farrenkopf Page 3 Relevant Aspects of Roller Compaction covering the Impact of Excipients, Milling Devices, Fines and
Feasibility Prediction
The intent was to possibly improve the good binder properties of MCC partially and to
reduce fines after milling. This target could be reached especially by two dry binders,
though associated with inherent drawbacks: already 3% PEG 1500 reduces the amount
of fines, keeps tablet disintegration time and improves milling batch-to-batch variation –
if the tablets crushing strength reduction by 20% is acceptable. 9% PVP K30 is required
for fines reduction by 6.1%, the best overall result. Tablets crushing strength is still
intact, batch-to-batch variation improved, but disintegration time is more than three
times higher than the compendial 15 minutes limit (for the assessed formulation,
intentionally manufactured without superdisintegrants).
To learn more about excipients for roller compaction, compression trials were performed
with pure excipients and rather formulation-like 1:1 blends with MCC. The objective was
to get information about the manufacturing methods comparability (direct tabletting vs.
roller compaction/tabletting vs. texture analyzer, TA) and the extend of their
predictability. The tablet’s crushing strength of each formulation is calculated by using
the slope’s formula for data standardization and direct comparison in a metric ranking
order, like for the three different sets of TA data.
Overall, the direct tabletting data prove to be predictable with a relatively high probability
from TA compression of powders. To a limited extend this is also valid for prediction of
roller compaction feasibility, using direct tabletting trials as well as the three TA
characterization systems. Here the TA compression of powders is preferred if only a
limited amount of material is available. If time is more critical than material availability, a
roller compaction trial should be considered in order to manufacture a few intact ribbons
at different compaction force levels. As milling and tabletting of the ribbons can be
skipped by simply assessing the ribbons properties with the TA, this approach can be a
valuable tool especially for screening purposes. As an outlook, the DT/RC prediction by
TA application could be improved further by overcoming TA speed limitations - thus
mimicking more closely DT/RC displacement and densification curves.
Looking into the excipients, MCC of adequately small d50 (type Avicel PH 101) reaches
the best scores for direct tabletting and roller compaction / tabletting and justifies being
the basic ingredient of roller compaction formulations. In contrast to that, the much
larger particles of Avicel PH 200 are not appropriate for this process. Despite its poor
performance as pure excipient in direct tabletting and roller compaction / tabletting,
Tablettose 70 shows unexpectedly good results in the 1:1 blend with Avicel PH 101, so
this combination can be considered for formulation development. To reduce fines,
mannitol (type Pearlitol SD 200) and pregelatinized starch (type Cerestar 93000) do not
seem to be well suited for roller compaction purposes, but the latter can help as tablet
disintegration aid in low proportions.


Page 4 Jochen Farrenkopf Relevant Aspects of Roller Compaction covering the Impact of Excipients, Milling Devices, Fines and
Feasibility Prediction
Kurzfassung der Ergebnisse

Bei der Walzenkompaktierung handelt es sich um ein Trockengranulationsverfahren. Es
wird eingesetzt um ungünstige Wirkstoff- oder Rezeptureigenschaften zu verbessern,
wie z.B. schlechte Fließeigenschaften, niedrige und/oder inhomogene Schüttdichte oder
Segregation/Aufschwimmen von Rezepturbestandteilen. Vereinfacht beschrieben wird
Pulver von zwei Rollen zu einer theoretisch unendlich langen Schülpe verdichtet,
welche umgehend zu Granulat zerkleinert wird. Durchdachter Geräteaufbau und
hochentwickelte Instrumentierung ermöglichen reproduzierbare, kontinuierliche
Herstellweise sowie PAT- und QbD-Anwendungen. Obwohl die Walzenkompaktierung
viele Vorteile bietet, besteht die Gefahr eines relativ hohen Feinanteils nach dem
Aufmahlen der Schülpen. Zur Beurteilung möglicher Auswirkungen wurde eine Vielzahl
von Mischungen aus feinen, mittleren und groben Granulatfraktionen hergestellt, um
eine praxisrelevante Auswahl verschiedener Korngrößenverteilungen zu simulieren.
Wie schon für die einzelnen Granulatfraktionen gezeigt werden konnte, verschlechterte
die Anwesenheit größerer Mengen Feinanteils < 0,1 mm deutlich die
Fließeigenschaften der Mischungen. Verglichen mit den unbehandelten Primärpartikeln
waren die Werte dennoch besser, eine weitere Verbesserung war bei den Mischungen
mit mittleren und groben Granulatfraktionen festzustellen. Es konnte experimentell