Posts

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Abstract

Amorphous solid dispersions layered pellets solve a problem of poorly water soluble drugs. Speaking about oral drug formulations, drug carrier solutions based on starter cores are suitable for several drug classes and open new opportunities for modified drug release profiles. Layering and coating techniques, such as Wurster fluid bed process at different batch sizes, are well established.

However, an increasing number of poorly water soluble drugs challenges modern formulations. A novel approach improving the solubility of those drugs is to formulate them as amorphous solid dispersions (ASD) with a suitable polymer candidate [1]. In this study, Nifedipine was used as a model drug. Nifedipine manages angina, high blood pressure, Raynaud’s phenomenon, and premature labor [2].

Formulation & techniques

ASD formulations can be performed by hot-melt extrusion or spray drying technique. Both techniques have disadvantages such that hot-melt extrusion cannot be employed for temperature-sensitive drugs [3], and spray drying needs a further compaction step not to result in fine powder with poor flowability, broad particle size distribution and high sensitivity to electrostatic charge. Therefore, a further compaction step is required to obtain a freely flowable product [4].

In this context, two techniques for the preparation of ASDs are compared: A 6”-Wurster fluid bed with Type-C bottom plate (Glatt, Germany) and spouted bed (ProCell5™ with Zig-Zag-sifter, Glatt, Germany) are used.

A: GF3™ (fluidized bed); B: ProCell5™ (spouted bed)

Fig. 1: A: 6”-Wurster fluid bed; B: ProCell5™ spouted bed.

The formulation contains the drug and a stabilizing co-polymer (Kollidon®, KVA64, BASF, Germany). Nifedipine and Kollidon are mixed resulting in a drug load of 40 % (w/w) and dissolved in Acetone (30 % w/w solid content).

Parameter FB SB
Spray rate [g/min] 20 20-35
Product temp. [°C] 50-60 50-60
Process gas temp. [°C] 65 80
Process air flow [m³/h] 180-200 65-120
Spraying nozzle diameter [mm] 1.2 1.2
Spraying pressure [bar] 2.0 0.5

Table 1: Manufacturing parameters for fluid bed (FB) and spouted bed (SB).

In the fluid bed process, microcrystalline pellets (Cellets® 500, IPC Dresden, Germany) were layered with the spraying solution such that a drug load of 21.8 % (w/w) is reached. In the spouted bed process, fine powder is generated by spray drying, further agglomeration and layering. An overview on the process parameters is given in Table 1.

Dissolution Tests

Dissolution tests were conducted in a PBS buffer at pH 6.8 and 37 °C (± 0.5 °C). A physical mixture of Nifedipine and KVA64 (40 % w/w drug load) is used as reference.

Results

In the following, results from both experiments, which are amorphous solid dispersions layered pellets (fluid bed) and ASD pellets from direct palletization (spouted bed) are compared.

Flowability and particle size

ASD layered pellets show a better sphericity, higher level of monodispersity and better flowability properties than the ASD pellets from direct palletization (Figure 2). Nonetheless, it has to be pointed out that both techniques result in a high particle quality for capsule filling. Analysis data is shown in Table 2.

Parameter FB SB
10 [µm] 824 ± 23 559 ± 28
D50 [µm] 943 ± 13 732 ± 50
D90 [µm] 1091 ± 11 1374 ± 410
Bulk density [g/L] 427 280
Flowability [s/100g] 12.1 16.2

Table 2: Analysis of ASD layered pellets (FB) and ASD pellets from direct compaction (SB).

SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

Fig. 2a: SEM images of processed pellets. A: ASD layered pellets based on Cellets® (FB)

SEM images of processed pellets. B: ASD pellets from direct palletization (SB)

Fig. 2b: SEM images of processed pellets. B: ASD pellets from direct palletization (SB)

Dissolution profiles

Independent from the processing technique, pellets achieved an approximately factor 2 higher end concentration than the physical mixture. Pellets obtained from the fluid bed process showed a clear supersaturation phase after 1 hour and a generally higher dissolution rate than pellets obtained from the spouted bed process. Contrarily, the dissolution rate of the latter pellets approaches the supersaturation phase more continuously after 3 hours.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Fig. 3: Dissolution as a function of time. Black: ASD layered pellets (FB). Red: ASD pellets from direct pelletization (SB). Blue: physical mixture.

Summary

Both techniques, fluid bed and spouted bed as well, can be employed for manufacturing amorphous solid dispersions with good flow properties and dissolution profiles. Both techniques can be scaled up to pilot and production scale for batch or continuous manufacture of freely flowable ASDs. Cellets® serve stable and reliable cores for this venture.

Acknowledgement

We gratefully acknowledge Dr. Annette Grave and Dr. Norbert Pöllinger (Glatt Pharmaceutical Services, Germany), and Prof. Karl G. Wagner and Marius Neuwirth (University Bonn, Germany).

References

[1] T. Vasconcelos, B. Sarmento, and P. Costa, Drug Discovery Today, 12(23): 1068-1075 (2007)

[2] “Nifedipine”. The American Society of Health-System Pharmacists. Retrieved: Sept 17, 2019.

[3] J. Breitenbach, European Journal of Pharmaceutics and Biopharmaceutics, (54)2: 107-117 (2002)

[4] I. Weuts et al., Journal of Pharmaceutical Sciences, (100)1: 260-274 (2011)

CS_hydrocortisone_image_5

Abstract

Hydrocortisone is found on the EMA unmet medical need priority list (2011) for the use in paediatric population for children suffering from all forms of adrenal insufficiency. Although there is a particular need in neonates and in infants, i.e. children younger than two years, there is a main issue. No licensed hydrocortisone preparation for paediatric use is available in Europe. Within the TAIN program (treatment of adrenal insufficiency in neonates and infants) supported by the European Commission [1], oral drug dosage research has been initiated.

Issues on Hydrocortisone

Hydrocortisone can be given orally, topically, or by injection [2]. After oral administration, free cortisol passes easily through cellular membranes which explains its 100% bioavailability [3]. Paediatrics key characteristics are taste masking (Figure 1) and the requirement of dedicated dosing units. Also the immediate drug release shell be comparable to crushed Hydrocortisone tablets.

CS_hydrocortisone_image_1

Taste masking increases customer compliance of bitter actives in paediatrics.

Transforming these requirements into a development strategy, following focus points need to be considered:

  1. Dosage change by multiparticulates
  2. Layering/coating of starter beads demands narrow size distribution and defined smooth surfaces.

These considerations exclude working on standard dry powder forms like rough granules, but recommend the usage of pellets. We will focus on pellets made of microcrystalline cellulose (MCC), which are Cellets® 350. The main advantage of these MCC pellets are narrow size distribution, smooth surface and chemical inertness. By spray coating, functional layers are coated onto the MCC pellet (Figure 2). Different drug loads can be achieved.

CS_hydrocortisone_image_2

Coated MCC pellet (green). Functional layers: hydrocortisone (blue), seal coat (orange), taste masking (grey).

A concept and selection of feasible excipients provide Cellets® as starter beads, cellulose derivates as binder, seal coating and taste masking.

The size distribution of Cellets® 350 is known to be highly narrow (Figure 3). Also critical parameters, such as sphericity and smoothness of the surface are almost perfect which is presented by an electron microscopy image in Figure 4. In turn, a subsequent precise layering of the active and adjustment of optimal time release profiles is possible.

CS_hydrocortisone_image_3

Size distribution of MCC pellets, type Cellets® 350.

CS_hydrocortisone_image_4

Electron microscopy image of a Cellets® 350 starter beads. A high degree of sphericity and a smooth surface are advantages of these starter beads.

CS_hydrocortisone_image_5

Finalized hydrocortisone pellets. Embedded pictures: electron microscopy image of a hydrocortisone pellet (top) and cross section (bottom).

After processing the hydrocortisone pellets are finalized and look – as the Cellets starter beads do – perfectly spherical with a smooth surface (Figure 5).

Summary

In this case study hydrocortisone by means of use in paediatric population for children suffering from all forms of adrenal insufficiency was investigated. Based on Cellets® 350 starter beads, multi-layering hydrocortisone pellets were manufactured with five dosage strengths between 0,5 mg and 10 mg. Extremely bitter API was successfully taste masked and a fast dissolution profile was obtained. Clinical trial material was produced for Phase I study.

Acknowledgement

We acknowledge Fraunhofer IFAM (Dresden, Germany) and University of Basel (Basle, Switzerland) for providing the electron microscopic images.

Authors

Dr. Bastian Arlt

References

[1] http://tain-project.org/

[2] Hydrocortisone, https://www.drugs.com/ (2016)

[3] M.C. Caldato, V.T. Fernandes, C.E. Kater, Arquivos Brasileiros De Endocrinologia E Metabologia. 48 (5), (2004) 705-712.

Theophylline size distribution

Abstract

Theophylline is a powerful active used for the acute treatment of respiratory distress. Its bioavailability and uptake rates are high. Drug carrier systems are pellets made of sugar or microcrystalline cellulose (MCC). This case study will point on the specific advantages of MCC pellets.

Layering on starter pellets

Basically, theophylline is an alkaloid that occurs in nature together with other purine alkaloids such as caffeine and theobromine, but it occurs in comparably small fractions up to 0.25 %. Anyhow, it can be synthetically composed. In application, theophylline is used for the acute treatment of respiratory distress due to airway constriction in bronchial asthma and other obstructive airway diseases.

After oral administration theophylline is rapidly and completely absorbed in the gastrointestinal tract (GIT). Retard preparations are used for long-term treatment, reaching their maximum effect after around six to eight hours [1].

Typical carrier systems are sugar and MCC pellets (Cellets®). By subsequent layering, retard and individual release profiles can be achieved. For both types of starter pellets, a drug solution for 200 g pellets (batch size) was formulated in the following way as listed in Table 1.

Parameter weighted mass
theophylline 8.32 g
PVP K30 0.67 g
distilled water 80.0 g
ammonia 25 % 4.0 g

Table 1: Substances for a drug solution for 200 g batch size.

Process Technology

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

Finalized pellets

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

Theophylline size distribution

Theophylline size distribution

Figure 1: Analysis of batches. From left to right: (1) best batch sugar pellets, (2) worst batch sugar pellets, (3) best batch Cellets®, (4) worst batch Cellets®.

Summary

In this case study, the coating of pellets with theophylline was investigated. A targeted drug load of 4.2 % was reached. By sophisticated formulation, further improvements towards optimized release profiles of the active in the GIT can be performed. Here, MCC pellets are superior to sugar pellets in terms of reproducibility, process time and quality rating after coating.

Acknowledgement

We acknowledge Dr. Riedel (Bayer) for assisting this case study.

Authors

Authors: Dr. Bastian Arlt

References

[1] B. Lemmer, R. Wettengel: Erkrankungen der Atemwege. In: B. Lemmer, K. Brune: Pharmakotherapie – Klinische Pharmakologie. 13. Auflage. Heidelberg 2007, ISBN 978-3-540-34180-2, S. 343–344, S. 349–350.