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Fuji_email blast_f-melt_feb16.2011.indd

F-MELT series, Issue2, February 2011 Formulating Taste Masked
and High Quality ODT of
Poorly Water Soluble Drugs
In this paper, we present case studies with taste masking technology and application of wet granulation technologies to develop ODTs of Loratadine, a water insoluble drug, and Famotidine, a slightly water soluble drug with bitter taste. Wet granulation approach was chosen to prepare ODTs of Loratadine and Famotidine and the tablets showed a very fast disintegration time as well as high dissolution rates. Bitterness of Famotidine could be eliminated by simple blending with fl avors and sweeteners such as sucralose, acesulfame potassium, and micronized menthol. F-MELT®, is a co-spray dried ODTs excipient system First appeared on developed by Fuji Chemical Industry Co., Ltd. It includes 5 market in 1980s, pharmaceutical excipients such as inorganic excipients, oral disintegrating carbohydrates and disintegrants. Currently more than 10 pharmaceutical and nutraceutical customers in US, continue to grow in Japan, India and Korea have launched ODTs with F- the pharmaceutical MELT® and approximately 40 customers around the industry. Market world are developing their ODTs formulations with F- research estimates MELT®. The common therapeutic targets of ODTs include allergies, nausea, migraine, schizophrenia, Alzheimer, reach 2.56 billion USD in 2012 and up to 3.9 billion USD by gastric ulcer, diabetes, hypertension, anticoagulant, 2017 (1). More and more pharmaceutical and nutraceutical anti-cholesterol, antihistamines, sedatives, anti- companies are opting ODTs to differentiate generics as emetics, cough/cold preparations, anesthetics, breath- well as extend product lines. Generally accepted tablet fresheners/oral anti-septics, and pet drugs. Most of qualities of ODTs include a tablet weight of less than these drugs are bitter, which needs taste masking.
500 mg, a tablet hardness of approximately 50 N and a disintegration time of 30 seconds. US FDA guidance specifi es that ODTs disintegrate rapidly in the oral cavity Fuji offers a choice of three different F-MELT® grades to within a matter of seconds when placed on the tongue, formulators worldwide. F-MELT® family includes type C, or approximately 30 seconds or less in vitro(2). Today, suitable for pharmaceutical and nutraceutical applications, several platforms are available to the manufacturer type M suitable for pharmaceutical applications, and F- of ODTs and the preference is tilting towards directly MELT® F1 for dietary supplement as well as functional compressible excipient systems. However, for poorly food applications (Table 1). With F-MELT®, formulators can water soluble drugs, wet granulation may still be the make high quality ODTs with high tablet hardness, good right choice for the manufacture of ODTs.
mouth feel and achieve disintegration time of less than 30 F-MELT series, Issue2, February 2011 seconds. In certain cases, high API load formulations (40- Table 2. The F-MELT® Features
50%) may reduce tablet performance such as reduction Ready to use excipient for ODTs
of tablet hardness and increase of disintegration time. For Oral disintegration time less than 30 seconds
example, increasing compression force to compensate Spherical shape with high fl owability
tablet hardness could increase disintegration time. With F- Directly compressible
MELT®, formulators can improve tablet qualities by simply API loading more than 50% possible
switching to different lubricants and/or incorporating an Tablet hardness more than 50 N possible with little
additional excipient. In addition, preparing tertiary particles or no sticking/capping
of APIs with F-MELT® by wet granulation using water or Pleasant mouth feel
solvent could be a proper strategy to improve the quality No royalty or license fees required
and performance of ODTs (Fig. 1).
No special equipment required for tabletting
Easy handling and storage of ODTs with low friability
Table 1. Ingredients of F-MELT® Family
F-MELT® Type C
F-MELT® Type M
F-MELT® F1
Pharmaceutical and Nutraceutical and Dietary supplement applications LORATADINE ODTs FORMULATION
WITH F-MELT® TYPE M
Microcrystalline Microcrystalline Microcrystalline A SUCCESSFUL EXAMPLE WITH
Loratadine is a water Aluminometasilicate Anhydrous (Fujicalin®) Anhydrous (Fujicalin®) insoluble drug belonging to antihistamine category, Figure 1. Flow Chart for Preparing High Quality ODTs with
a target for ODTs market. Loratadine crystal particle size is less than 10 μm while route with water or F-MELT® mean particle size (D50) is 120 μm. F-MELT®
Dry blending of F-MELT® or other excipients with compression route such low particle size APIs always pose big challenge to formulators. Wet granulation of Loratadine was attempted with both water and organic solvent. Water and/or solvent (water:ethanol=7:3) granulation of Loratadine was carried Tablet Hardness: Approx. 50 N out with a portion of F-MELT® Type M (ratio 1:5). The granules were passed through No.25 sieve (710 μm) and dried overnight at 55°C. The dried granules were further passed through a No.60 sieve (250 μm) and blended with additional F-MELT® Type M and lubricant to prepare ODTs. The ODTs showed suffi cient hardness (approx. 50N) and a disintegration time of less than 30s (Table 3). Addition of excipients
Change of lubricant
Dissolution was 99% with water granulation and 100% with (Eg: HPS, MCC, CMC, (Eg: from Mg-St to Fu-Na) solvent granulation (Fig 2). Granulating with 30% ethanol increased content uniformity (100%) when compared to water granulation (97%) of Loratadine with F-MELT® Type M. Dry blending and direct compression of Loratadine with High Quality ODT
same amount of F-MELT® type M resulted in poor content Sufficient tablet quality & performance uniformity and dissolution (data not shown).
F-MELT series, Issue2, February 2011 Table 3. Loratadine ODTs Formulations with F-MELT® Type M
TASTE MASKED FAMOTIDINE ODTs
FORMULATION WITH F-MELT®,
Water-granulated Loratadine with A SUCCESSFUL EXAMPLE WITH
F-MELT® Type M (1:5) Solvent-granulated Loratadine with F-MELT® Type M (1:5) Taste masking is more necessary and important to Magnesium Stearate success of ODTs products on the market. Available taste masking technologies include use of fl avors and sweeteners, coating of drug particles Tablet hardness (N) with inert materials, formation of inclusion complexes, Pharmacopoeia disintegration time (s) molecular complexes of drug with other chemicals, Oral disintegration time ODT-101*(s) microencapsulation, multiple emulsions, prodrugs, Tablet condition: Ф 8 mm, 200 mg/Tab, Rotary tabletting machine*Equipment to measure ODTs (Toyama Sangyo Co., Ltd.) liposomes, dispersion coating, and ion exchange resins. These technologies are not only used to mask the taste of drugs but also to enhance the bioavailability of drugs. Figure 2. Dissolution Profi le of solvent granulated (SG)
Loratadine ODTs Formulation
Among these technologies, use of fl avors and sweeteners is simpler, cost effective, and suitable with F-MELT®. Sweeteners and fl avoring agents can be natural or Loratadine F-MELT® SG ODT synthetic such as peppermint, lemon oil, clove, balsam, stevia, aspartame, sucralose, neotame, acesulfame potassium, sucrose, sorbitol, xylitol, saccharin, and others. F-MELT® already contains xylitol which partly contributes to good taste of ODTs. Furthermore, depending on APIs, Dissolution rate (%) formulators can add other sweeteners and fl avors in order to minimize the bitterness of APIs. Famotidine belongs to a group of drugs called histamine (H2) blockers. It works by decreasing the amount of acid that stomach produces. Famotidine is bitter in taste and need taste masking in Dissolution was carried out with JP disintegration test solution #1 (pH 1.2), 900 ml, 37°C, paddle speed 50 rpm.
order to be acceptable to patients who suffer from ulcers in the stomach or intestines.
Stability tests of solvent granulated Loratadine F-MELT® ODTs were carried out for one week at RT (25°C) and Water granulation of Famotidine was carried out with a 75% RH under open conditions. The tablets retained portion of F-MELT® Type M (ratio 2:5). The granules were 87.81% of hardness and there was no drastic deviation passed through No.25 sieve (710 μm) and dried overnight with respect to pharmacopoeia or oral disintegration at 55°C. The dried granules were further passed through a times (Table 4).
No.60 sieve (250 μm) and blended with additional F-MELT® Type M, taste masking agents and lubricant to prepare Table 4. Stability Test of solvent granulated (SG) Loratadine
ODTs. Addition of 0.4% sucralose, 0.4% acesulfame potassium and 0.05% micronized menthol could eliminate 25°C, 75% RH,
Open, 1 week
the bitter taste of Famotidine. The ODTs showed suffi cient Tablet hardness (N) hardness (approx. 50N) and a disintegration time of less Compression force (kgf) than 30s (Table 5). Dissolution was almost 100% (Fig 3). Pharmacopoeia disintegration time (s) Dry blending and direct compression of Famotidine Oral disintegration time ODT-101* (s) with same amount of F-MELT® type M resulted in poor *Equipment to measure ODTs (Toyama Sangyo Co., Ltd.) content uniformity and dissolution (data not shown).
F-MELT series, Issue2, February 2011 Table 5. Famotidine ODTs Formulation with F-MELT® Type M
Wet granulation as a strategy to manufacture ODTs of Water-granulated Famotidine with F-MELT® Type M (2:5) poorly water soluble drugs proved to be a success with Loratadine and Famotidine ODTs. Wet granulation achieved overall quality of ODTs with respect to tablet hardness, Acesulfame potassium disintegration time and dissolution profi le. Taste masking Micronized menthol of Famotidine was achieved by simple blending of fl avors Magnesium stearate and sweeteners with F-MELT® Type M. In conclusion, wet granulation with F-MELT® could be an excellent approach to produce ODTs of poorly water soluble drugs which are Tablet hardness (N) Pharmacopoeia disintegration time (s) Oral Disintegration time ODT-101*(s) Tablet condition: Ф 8 mm, 200 mg/Tab, Rotary tabletting machine*Equipment to measure ODTs (Toyama Sangyo Co., Ltd.) 1. Bill Martineau 2009. A look at Fast-dissolving drug delivery system. Drug Delivery Technology. 36-38 2. FDA, Guidance for Industry: Orally disintegrating tablets (Rockville, MD, Dec. 2008) Eng. 18, 163–168.
Figure 3. Dissolution Profi le of water granulated (WG)
Famotidine ODTs Formulation
PHARMACOPOEIA & REGULATORY
Famotidine F-MELT® WG ODT Type C meet all requirements of the current USP/NF, JP and EP US DMF Type IV filed in January 2007 # 20084 Type M meets all requirement of the current USP/NF, JP Japan Patent No.3841804 August 18, 2006.
Patented in Japan, India, USA and China. Patend pending in Korea and EU.
Dissolution rate (%) Dissolution was carried out with distilled water 900 ml, 37°C, paddle speed 50 rpm.
Stability tests of water granulated Famotidine F-MELT® ODTs were carried out for one week at RT (25°C) and 75% RH under open conditions. The tablets retained 98.29% of tablet hardness and there was no drastic deviation with respect to pharmacopoeia or oral disintegration times The information found in this publication is presented in good faith with no guarantee or obligation as to accuracy and no assumption of liability. Users should make their own tests to determine the Table 6. Stability Test of water granulated (WG) Famotidine
suitability of these products for their own particular purposes. However, ODTs Formulation
because of numerous factors affecting results, Fuji Chemical Industry makes no warranty of any kind, express or implied, including those 25°C, 75% RH,
Open, 1 week
of merchantability and fitness for particular purpose other than the material conforms to its applicable current standard specifications. Tablet hardness (N) Statements concerning the use of the products or formulations described herein are not to be construed as recommending the Compression force (kgf) infringement of any patent and seller assumes no liability for the Pharmacopoeia disintegration time (s) infringement arising out of such use.
Oral disintegration time ODT-101* (s) F-MEL is a trademark or registered trademark of Fu is a trademark or registered trademark of F ji Chemical Industry Co.
y Co , Ltd. in Japan, ., Ltd. in Japan United States of America, , United States of America, *Equipment to measure ODTs (Toyama Sangyo Co., Ltd.) Europe and/or other countries.
Europe and/or other countries.

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