Liqui-pellet: the emerging next-generation oral dosage form which stems from liquisolid concept in combination with pelletization technology

In spite of the major advantages that the liquisolid technology offers, particularly in tackling poor bioavailability of poorly water-soluble drugs (i.e., BCS Class II drugs), there are a few critical drawbacks. The inability of a high liquid load factor, poor flowability, poor compactibility, and an inability to produce a high dose dosage form of a reasonable size for swallowing are major hurdles, hampering this technology from being commercially feasible. An attempt was therefore made to overcome these drawbacks whilst maintaining the liquisolid inherent advantages. This resulted in the emerging next generation of oral dosage forms called the liqui-pellet. All formulations were incorporated into capsules as the final product. Solubility studies of naproxen were conducted in different liquid vehicles, namely polyethylene glycol 200, propylene glycol, Tween 80, Labrafil, Labrasol, and Kolliphor EL. The scanning electron microscopy studies indicated that the liquid vehicle tends to reduce the surface roughness of the pellet. X-ray powder diffraction (XRPD) indicated no significant differences in the crystalline structure or amorphous content between the physical mixture and the liqui-pellet formulation. This was due to the presence of a high concentration of amorphous Avicel in the formulation which overshadowed the crystalline structure of naproxen in the physical mixtures. Flowability and dissolution tests confirmed that this next-generation oral dosage form has excellent flowability, whilst maintaining the typical liquisolid enhanced drug release performance in comparison to its physical mixture counterpart. The liqui-pellet also had a high liquid load factor of 1, where ~ 29% of the total mass was the liquid vehicle. This shows that a high liquid load factor can be achieved in a liqui-pellet without compromising flowability. Overall, the results showed that the poor flowability of a liquisolid formulation could be overcomed with the liqui-pellet, which is believed to be a major advancement into the commercial feasibility of the liquisolid concept

Wet granulation in laboratory-scale high shear mixers: Effect of chopper presence, design and impeller speed

The effect of the main means of agitation in a high shear mixer has been investigated in this study. Granulation runs have been performed on a fine cohesive microcrystalline cellulose powder (Avicel 105, d50 = 20 μm) often used as a pharmaceutical excipient in tablet formulations in two bowls of a Mi-Pro® laboratory high shearmixer with a capacity of 0.9 and 1.9 L, respectively. Torque curves recorded during granulation are found to allow good control of the process while increasing impeller speed is found to generally reduce granule size and the onset of breakage seems to occur for similar values of impeller tip speed. As a general rule, the chopper allows for better binder distribution in the Mi-Pro® and is found to be necessary for successful granulation at low to moderate impeller speeds. For high impeller speeds in excess of 4.4 m/s with or without a chopper, similar granule sizes and growth mechanisms are observed. Granule roundness was found to increase with impeller speed up to a certain speed after which granule roundness has been found to decrease with increasing impeller speed most probably because of increased breakage of the granules. Dry granule strength has been found to increase with increasing impeller speed, presenting only a slight decrease at the highest impeller speed studied

Influence of process variables on the properties of simvastatin self-emulsifying granules obtained through high shear wet granulation

Improvements of the oral bioavailability of lipophilic drugs can be obtained using lipidic formulations such as the self-emulsifying drug delivery systems. The high shear wet granulation (HSWG), using microemulsions as binder, is a viable process to produce self-emulsifying granules. However only few information are present in the literature on the effect of process variables on the properties of the granules obtained with these binders. Consequently, this article compares the effects of some relevant experimental variables (impeller speed and massing time) on thefinal technological and pharmaceutical properties of the granules produced using simple water, or alternatively, a microemulsion as binder and containing simvastatin (SV) as model drug. The effects of the variables were determined by evaluating the granule median diameter, their particle size distribution, roundness, disintegration time and dissolution rate of SV. Results clearly demonstrated that the microemulsion-based process was less sensitive tooperating conditions than the water-based process. With microemulsion the nucleation process and growth regimes were more difficult to control, resulting in products with broader PSDs. At the same operatingconditions microemulsion-based granules were more brittle but rounder and showed smaller median diameter compared to water-based granules. The dissolution rate of simvastatin was not significantly affected by the operating conditions

Pengaruh Waktu Sferonisasi Terhadap Sifat Fisik Pelet Yang Dibuat Menggunakan Metode Ekstrusi-sferonisasi

Amilum singkong pregelatin dapat digunakan sebagai eksipien pelet karena dapat bersifat sebagai bahan pengikat untuk menghasilkan pelet yang tidak mudah hancur, selain itu amilum singkong pregelatin dapat bersifat sebagai bahan penghancur yang bertujuan untuk melepaskan kandungan bahan obat di dalamnya. Pada tahap sferonisasi, kecepatan putaran sferoniser dan waktu sferonisasi berpengaruh terhadap kualitas pelet yang dihasilkan. Kecepatan sferonisasi yang digunakan adalah 400 rpm dengan lamanya waktu sferonisasi yang bervariasi antara 2 hingga 15 menit. Tujuan penelitian ini untuk mengetahui pengaruh waktu sferonisasi terhadap sifat fisik pelet yang dibuat menggunakan metode ekstrusi-sferonisasi. Massa plastis dihasilkan dari perbandingan bahan amilum singkong pregelatin : parasetamol : air (15 : 1 : 10). Semua bahan kemudian diekstrusi, ekstrudat yang terbentuk dikeringkan dalam oven 50ºC selama 20 menit lalu disferonisasi menggunakan kecepatan 400 rpm dengan variasi waktu 5, 10, dan 15 menit. Pelet dikeringkan dalam oven 50ºC selama 30 menit. Evaluasi pelet meliputi perhitungan rendemen pelet, ukuran pelet, bentuk pelet, kelembaban pelet, sifat alir pelet, kompresibilitas pelet, dan kerapuhan pelet. Variasi waktu sferonisasi menunjukkan perbedaan yang signifikan terhadap rendemen dan ukuran pelet (p < 0,05). Semakin lama waktu sferonisasi, rendemen pelet yang dihasilkan semakin sedikit dan ukuran pelet akan semakin besar. Pelet yang dihasilkan dari masing-masing waktu sferonisasi hanya memenuhi kriteria pada penentuan ukuran dan pengujian kompresibilitas pelet, sedangkan pada pengujian sifat fisik lainnya masih belum memenuhi kriteria sifat fisik pada pustaka

Enteric coated spheres produced by extrusion/spheronization provide effective gastric protection and efficient release of live therapeutic bacteria

We present a novel but simple enteric coated sphere formulation containing probiotic bacteria (Lactobacillus casei). Oral delivery of live bacterial cells (LBC) requires live cells to survive firstly manufacturing processes and secondly GI microbicidal defenses including gastric acid. We incorporated live L. casei directly in the granulation liquid, followed by granulation, extrusion, spheronization, drying and spray coating to produce dried live probiotic spheres. A blend of MCC, calcium-crosslinked alginate, and lactose was developed that gave improved live cell survival during manufacturing, and gave excellent protection from gastric acid plus rapid release in intestinal conditions. No significant loss of viability was observed in all steps except drying, which resulted in approximately 1 log loss of viable cells. Eudragit coating was used to protect dried live cells from acid, and microcrystalline cellulose (MCC) was combined with sodium alginate to achieve efficient sphere disintegration leading to rapid and complete bacterial cell release in intestinal conditions. Viability and release of L. casei was evaluated in vitro in simulated GI conditions. Uncoated spheres gave partial acid protection, but enteric coated spheres effectively protected dried probiotic LBC from acid for 2 h, and subsequently released all viable cells within 1h of transfer into simulated intestinal fluid

Sifat Fisik Pelet Parasetamol Yang Dibuat Dengan Metode Ekstrusi-sferonisasi: Pengaruh Suhu Pengeringan

Amilum singkong pregelatin merupakan salah satu alternatif eksipien dalam pembuatan pelet. Selain sebagai pengikat dan penghancur, amilum pregelatin mampu larut dalam air sehingga dapat membentuk massa basah yang plastis yang dibutuhkan dalam pembuatan pelet. Pengeringan pelet merupakan tahap akhir dalam pembuatan pelet yang menentukan sifat fisik pelet. Penelitian ini bertujuan untuk melihat pengaruh suhu pengeringan pelet terhadap sifat fisik pelet bereksipien amilum singkong pregelatin. Pelet dibuat menggunakan metode ekstrusi-sferonisasi dengan perbandingan parasetamol : amilum singkong pregelatin : akuades yaitu 1 : 15 : 10. Massa basah yang dihasilkan dari pencampuran bahan-bahan tersebut diekstrusi, kemudian dilanjutkan dengan sferonisasi ekstrudat dengan kecepatan 400 rpm selama 10 menit. Pelet yang dihasilkan dikeringkan pada oven dengan variasi suhu yaitu 50, 55, dan 60 °C selama 30 menit. Pelet dievaluasi melalui pengujian ukuran, bentuk, kelembaban, sifat alir, kompresibilitas, dan kerapuhan. Data yang diperoleh diuji menggunakan statistik ANOVA dengan taraf kepercayaan 95%. Dari hasil penelitian diperoleh bahwa suhu pengeringan pelet berpengaruh signifikan terhadap ukuran, bentuk kelembaban, kompresibilitas, dan kerapuhan pelet. Semakin tinggi suhu pengeringan akan menurunkan ukuran, kelembaban, kompresibilitas, dan kerapuhan pelet namun akan meningkatkan derajat sferisitas

Uji Pendahuluan Formula Pelet Effervescent dengan Variasi Konsentrasi Polivinil Pirolidon (Pvp) sebagai Bahan Pengikat

Pelet effervescent merupakan sediaan yang dapat dibuat terpisah antara komponen paket asam dan paket basa namun dapat dikemas dalam satu wadah yang sama, sehingga tidak memerlukan kondisi suhu dan kelembapan ruangan yang terkendali untuk menekan reaksi kimia asam basa saat proses pembuatan. Pada formulasi pelet effervescent dilakukan uji pendahuluan yang meliputi uji organoleptis effervescent serta pengujian bentuk, dan ukuran pelet. Uji pendahuluan adalah uji tahap awal yang dilakukan untuk mengetahui pengaruh dari variasi konsentrasi pengikat terhadap sifat fisik pelet dan sifat organoleptis effervescent serta untuk memastikan bahwa sediaan yang dibuat sesuai dengan definisi sediaan pelet effervescent. Penelitian ini merupakan penelitian eksperimental untuk melihat pengaruh dari variasi konsentrasi pengikat terhadap sediaan pelet effervescent yang ditunjukkan dari hasil uji pendahuluan. Pelet effervescent akan dibuat dengan metode ekstrusi sferonisasi, dimana dilakukan pemisahan antara paket asam dan paket basa. Paket asam terdiri dari asam tartrat, natrium sakarin, PVP, dan manitol. Sedangkan paket basa terdiri dari natrium bikarbonat, natrium karbonat, PVP, dan manitol. Kemudian akan dilakukan variasi konsentrasi pengikat yaitu polivinil pirolidon (PVP) sebesar 2-5% pada kedua paket. Tahapan selanjutnya yaitu melakukan pengujian homogenitas warna, sensasi rasa, bentuk, dan ukuran pelet effervescent. Hasil uji pendahuluan pelet effervescent menunjukkan tidak adanya pengaruh dari variasi konsentrasi pengikat yaitu PVP terhadap sifat fisik pelet effervescent, sehingga keempat formula dapat digunakan pada uji tahap lanjut untuk mendapatkan formula terbaik. Hasil ini berdasarkan pengujian pendahuluan yang meliputi homogenitas warna, sensasi rasa, bentuk pelet, dan ukuran pelet effervescent yang memenuhi persyaratan bentuk fisik pelet effervescent

Analysis of formulation effects in the dissolution of ibuprofen pellets

In this work the effects of citric acid and of two common fillers, lactose (soluble) and tricalcium phosphate (insoluble) are examined on the release profiles from pellets, using ibuprofen as a model drug with pH-dependent solubility. Also studied is the dependence of these profiles on the specific surface area, bulk density, apparent density, porosity and porosity parameters (pore size distribution, total pore surface area, mean pore diameter and pore shape), as determined by mercury intrusion porosimetry. Pellets with high porosity and total pore surface area but small median pore diameter (tricalcium phosphate pellets--IPM) are found to produce similar dissolution results to those of low porosity and low total pore surface area, but having a high median pore diameter (lactose pellets--ILM), irrespective of the solubility of excipients. Addition of citric acid causes a delay in the initial dissolution for both formulations. During dissolution, however, citric acid reduces the median pore diameter of lactose-based pellets. In contrast, in tricalcium phosphate/citric acid pellets (CIPM), this parameter increases considerably during dissolution, when compared to the IPM formulation. These findings may justify the contrasting dissolution behaviors of CIPM and CILM (lactose/citric acid) pellets, after their common behavior in the initial stages, and show that porosity and its related parameters, along with physical properties of excipients such as solubility, density and specific surface area, are helpful to predict pellet behavior in drug release profiles.http://www.sciencedirect.com/science/article/B6T7W-4B54142-4/1/d88c9200d18c56a3a1d6f0d0eb11578