formulation aspects in the development of orodispersible tablets
formulation aspects in the development of orodispersible tablets
formulation aspects in the development of orodispersible tablets
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Review Article<br />
FORMULATION ASPECTS IN THE DEVELOPMENT OF ORODISPERSIBLE TABLETS: AN<br />
OVERVIEW<br />
TAPAN KUMAR GIRI 1* , DULAL KRISHNA TRIPATHI 1 AND RANA MAJUMDAR 2<br />
1Rungta College <strong>of</strong> Pharmaceutical Sciences & Research, Kohka Road, Kurud, Bhilai491024, India, 2Calcutta Institute <strong>of</strong> Pharmaceutical<br />
Technology & Allied Health Sciences, Uluberia, Howrah711316, India Email: tapan_ju01@rediffmail.com<br />
Received: 26 April 2010, Revised and Accepted: 07 May 2010<br />
ABSTRACT<br />
Over <strong>the</strong> past three decades, <strong>orodispersible</strong> <strong>tablets</strong> (ODTS) have ga<strong>in</strong>ed considerable attention as a preferred alternative to conventional <strong>tablets</strong> and<br />
capsules due to better patient compliance. Upon <strong>in</strong>troduction <strong>in</strong>to <strong>the</strong> mouth, <strong>the</strong>se <strong>tablets</strong> dissolve or disperse <strong>in</strong> <strong>the</strong> mouth <strong>in</strong> <strong>the</strong> absence <strong>of</strong><br />
additional water and <strong>the</strong> active pharmaceutical <strong>in</strong>gredients are readily released from <strong>the</strong> dosage form. These <strong>tablets</strong> are convenient for young<br />
children, elderly and patients with swallow<strong>in</strong>g difficulties, and <strong>in</strong> situations where a potable liquid (water) is not available. Products <strong>of</strong> ODT<br />
technologies entered <strong>the</strong> market <strong>in</strong> <strong>the</strong> 1980s and have grown steadily <strong>in</strong> demand. Their product pipel<strong>in</strong>es are rapidly expand<strong>in</strong>g. The popularity<br />
and usefulness <strong>of</strong> <strong>the</strong>se <strong>formulation</strong>s resulted <strong>in</strong> <strong>development</strong> <strong>of</strong> several ODT technologies. In <strong>the</strong> present review <strong>the</strong> <strong>formulation</strong> techniques and<br />
different technologies are discussed.<br />
Keywords: Orodispersible <strong>tablets</strong>, dis<strong>in</strong>tegration time, superdis<strong>in</strong>tegrant, direct compression<br />
INTRODUCTION<br />
In recent years, considerable attention has been focused on <strong>the</strong><br />
<strong>development</strong> <strong>of</strong> novel drug delivery systems (NDDS). The reason for<br />
this paradigm shift may be due to relatively low <strong>development</strong> cost<br />
and time required for <strong>in</strong>troduc<strong>in</strong>g a NDDS ($ 20‐50 million and 3‐4<br />
years respectively) as compared to a new chemical entity<br />
(approximately $ 500 million and 10‐12 years, respectively). In <strong>the</strong><br />
form <strong>of</strong> NDDS, an exist<strong>in</strong>g drug molecule can get a ‘new life’, <strong>the</strong>reby<br />
<strong>in</strong>creas<strong>in</strong>g its market value, competitiveness, and patent life.<br />
Among <strong>the</strong> various NDDS available <strong>in</strong> market, <strong>orodispersible</strong> <strong>tablets</strong><br />
hold <strong>the</strong> major share because <strong>of</strong> <strong>the</strong>ir obvious advantages <strong>of</strong> ease <strong>of</strong><br />
adm<strong>in</strong>istration and better patient compliance. Difficulty <strong>in</strong><br />
swallow<strong>in</strong>g a tablet or capsule is a common problem <strong>of</strong> all age<br />
groups, especially <strong>of</strong> elderly and paediatrics, because <strong>of</strong><br />
physiological changes associated with <strong>the</strong>se groups <strong>of</strong> patients.<br />
O<strong>the</strong>r categories <strong>of</strong> patients that experience problems <strong>in</strong> us<strong>in</strong>g<br />
conventional oral dosage forms <strong>in</strong>cludes <strong>the</strong> mentally ill,<br />
uncooperative, nauseated patients, and those with conditions <strong>of</strong><br />
motion sickness, sudden episodes <strong>of</strong> allergic attack or cough<strong>in</strong>g.<br />
Sometimes, it may be <strong>in</strong>convenient to swallow a conventional<br />
product due to unavailability <strong>of</strong> water. These problems led to <strong>the</strong><br />
<strong>development</strong> <strong>of</strong> novel type <strong>of</strong> solid oral dosage form called<br />
“<strong>orodispersible</strong> tablet”.<br />
ODTs are known by various names such as mouth dissolv<strong>in</strong>g, fast<br />
dissolv<strong>in</strong>g, fast melt<strong>in</strong>g, rapidly dis<strong>in</strong>tegrat<strong>in</strong>g, orally dis<strong>in</strong>tegrat<strong>in</strong>g<br />
<strong>tablets</strong>. The European pharmacopoeia def<strong>in</strong>es <strong>the</strong> term<br />
“orodisperse” as a tablet that can be placed <strong>in</strong> <strong>the</strong> mouth where it<br />
disperses rapidly before swallow<strong>in</strong>g1. Suitable drug candidates for<br />
such systems <strong>in</strong>clude neuroleptics, cardiovascular agents, analgesics,<br />
antiallergics and drugs for erectile dysfunction2.Such a tablet<br />
dis<strong>in</strong>tegrates <strong>in</strong>stantaneously when placed on tongue, releases <strong>the</strong><br />
drug that dissolves or disperses <strong>in</strong> <strong>the</strong> saliva. As <strong>the</strong> oral mucosa is<br />
highly vuscularised3, drugs that are absorbed through <strong>the</strong> oral<br />
mucosa can directly enter <strong>in</strong>to <strong>the</strong> systemic circulation, bypass<strong>in</strong>g<br />
<strong>the</strong> gastro<strong>in</strong>test<strong>in</strong>al tract (GIT) and <strong>the</strong>refore first‐pass metabolism<br />
<strong>in</strong> <strong>the</strong> liver. This result to a rapid onset <strong>of</strong> action4 , and greater<br />
bioavailability <strong>of</strong> <strong>the</strong> drug than those observed from conventional<br />
tablet dosage form5. Dur<strong>in</strong>g <strong>the</strong> last decade, several new advanced technologies have<br />
been <strong>in</strong>troduced for <strong>the</strong> <strong>formulation</strong> <strong>of</strong> ODTs with very <strong>in</strong>terest<strong>in</strong>g<br />
features, like extremely low dis<strong>in</strong>tegration time, exceptional taste<br />
mask<strong>in</strong>g ability, pleasant mouth feel and sugar free <strong>tablets</strong> for<br />
diabetic patients. Various technologies utilized for fabrication <strong>of</strong><br />
ODTs and <strong>the</strong>se techniques are based on <strong>the</strong> pr<strong>in</strong>ciples <strong>of</strong> <strong>in</strong>creas<strong>in</strong>g<br />
International Journal <strong>of</strong> Pharmacy and Pharmaceutical Sciences<br />
ISSN- 0975-1491 Vol 2, Suppl 3, 2010<br />
porosity by addition <strong>of</strong> superdis<strong>in</strong>tegrants and/or water soluble<br />
excipients <strong>in</strong> <strong>the</strong> <strong>tablets</strong>.<br />
Advantages <strong>of</strong> ODTs<br />
ODTs have <strong>the</strong> advantages <strong>of</strong> ease <strong>of</strong> adm<strong>in</strong>istration to <strong>the</strong> patient<br />
who cannot swallow, such as <strong>the</strong> elderly, stroke victims, bedridden<br />
patients, patient affected by renal failure and patient who refuse to<br />
swallow such as paediatric, geriatric and psychiatric patients. No<br />
need <strong>of</strong> water to swallow <strong>the</strong> dosage form, which is highly<br />
convenient for patients who are travell<strong>in</strong>g and do not have<br />
immediate access <strong>of</strong> water. From <strong>the</strong> pharmaceutical <strong>in</strong>dustry’s<br />
po<strong>in</strong>t <strong>of</strong> view, ODTs can provide new dosage forms as a life cycle<br />
management tool for drugs near <strong>the</strong> end <strong>of</strong> <strong>the</strong>ir patent life.<br />
Because, <strong>the</strong> <strong>tablets</strong> dis<strong>in</strong>tegrate <strong>in</strong>side <strong>the</strong> mouth, drugs may be<br />
absorbed from <strong>the</strong> pregastric area i.e., mouth, pharynx and<br />
oesophagus which may produce rapid onset <strong>of</strong> action6,7, prevent loss<br />
<strong>of</strong> drug due to first‐pass effect. Pregastric absorption can result <strong>in</strong><br />
improved bioavailability, reduced dose and improved cl<strong>in</strong>ical<br />
performance by reduc<strong>in</strong>g side effects8. Characteristics and <strong>formulation</strong> challenges <strong>of</strong> ODTs<br />
The key properties <strong>of</strong> <strong>the</strong> <strong>tablets</strong> are fast absorption or wett<strong>in</strong>g <strong>of</strong><br />
water <strong>in</strong>to <strong>the</strong> <strong>tablets</strong> and dis<strong>in</strong>tegration <strong>of</strong> associated particles <strong>in</strong>to<br />
<strong>in</strong>dividual components for fast dissolution. This requires that<br />
excipients should have high wettability, and <strong>the</strong> tablet structure<br />
should also have a highly porous network. Because <strong>the</strong> strength <strong>of</strong> a<br />
tablet is related to compression pressure, and porosity is <strong>in</strong>versely<br />
related to compression pressure, it is important to f<strong>in</strong>d <strong>the</strong> porosity<br />
that allows water absorption faster with ma<strong>in</strong>tenance <strong>of</strong> higher<br />
mechanical strength. ODTs should have low sensitivity to moisture<br />
for greater stability. A good package design or o<strong>the</strong>r strategy should<br />
be created to prevent ODTs from various environmental conditions2. For <strong>the</strong> ideal ODTs technology, <strong>the</strong> drug properties should not<br />
significantly affect <strong>the</strong> tablet property for example; <strong>the</strong> solubility,<br />
crystal morphology, particle size, hygroscopicity, compressibility,<br />
and bulk density <strong>of</strong> a drug can significantly affect <strong>the</strong> f<strong>in</strong>al<br />
characteristics <strong>of</strong> <strong>tablets</strong>, such as porosity, tablet strength,<br />
dis<strong>in</strong>tegration and dissolution.<br />
As <strong>the</strong> ODTs dissolve or dis<strong>in</strong>tegrate <strong>in</strong> <strong>the</strong> patient’s mouth, <strong>the</strong> drug<br />
will be partially dissolved <strong>in</strong> close proximity to <strong>the</strong> taste buds. Thus,<br />
<strong>the</strong> taste <strong>in</strong>side <strong>the</strong> mouth becomes critical for patient acceptance.<br />
When <strong>the</strong> drug is tasteless or does not have an undesirable taste,<br />
taste mask<strong>in</strong>g techniques does not become so important. The taste‐<br />
mask<strong>in</strong>g technology should not affect <strong>the</strong> ODT <strong>formulation</strong>. There<br />
are various ODTs <strong>tablets</strong> available <strong>in</strong> <strong>the</strong> market (Table 1).
Giri et al.<br />
Int J Pharmacy and Pharm Sci, Vol 2, Issue 3, 3842<br />
Table 1: Commercially available ODT products<br />
Trade name Active <strong>in</strong>gredient Manufacturer<br />
Dolib MD R<strong>of</strong>ecoxib Panacea<br />
R<strong>of</strong>aday MT R<strong>of</strong>ecoxib Lup<strong>in</strong><br />
Orthoref MD R<strong>of</strong>ecoxib Biochem<br />
Torrox Mt R<strong>of</strong>ecoxib Torrent<br />
Benadryl Fast melt Diphenhydram<strong>in</strong>e Warner Lambert<br />
Kemstro Bacl<strong>of</strong>en Schwarz Pharma<br />
Imodium <strong>in</strong>stant melts Loperamide HCl Janssen<br />
Mosid MT Mosapride Torrent<br />
Domray MD Domperidone Ray Remedies<br />
Values Valdecoxib Glenmark<br />
Nimulid MD Nimusulide Panacea<br />
Zotacet MD Cetriz<strong>in</strong>e HCl Zota Pharma<br />
Romilast Montelukast Ranbaxy<br />
Olanex Instab Olanzep<strong>in</strong>e Ranbaxy<br />
Maxalt‐MLT Rizatriptan Benzoate Merck<br />
Febrectol Paracetamol Prographarm<br />
Pepcid ODT Famotid<strong>in</strong>e Merck<br />
Zyprexa Olanzap<strong>in</strong>e Eli lilly<br />
Z<strong>of</strong>ran ODT Ondansetron GSK<br />
Klonop<strong>in</strong> Wafers Clonaxepam Roche<br />
Zom<strong>in</strong>g ZMT Zolmitriptan Astra Zeneca<br />
Cibalg<strong>in</strong>adue FAST Ibupr<strong>of</strong>en Novartis Consumer Health<br />
Nulev Hyocyam<strong>in</strong>e sulphate Schwarz Pharma<br />
Benadryl Fastmelt Diphenhydram<strong>in</strong>e Pfizer<br />
Feldene melt Piroxicam Pfizer<br />
Tempra Quicklets Acetam<strong>in</strong>ophen Bristol Myers Squibb<br />
Kid Relief Acetam<strong>in</strong>ophen Ethypharm<br />
Clarit<strong>in</strong> Reditabs Loratid<strong>in</strong>e Scher<strong>in</strong>g‐Plough<br />
Zelapar TM Selegill<strong>in</strong>e Amar<strong>in</strong> Corp<br />
Risperdal Risperidone Janssen Pharmaceutica Products<br />
Techniques for prepar<strong>in</strong>g ODTs<br />
The various techniques are be<strong>in</strong>g utilized or adopted to prepare<br />
ODTs<br />
a) Direct Compression<br />
b) Sublimation<br />
c) Humidity treatment<br />
d) S<strong>in</strong>ter<strong>in</strong>g<br />
e) Wet Granulation<br />
f) Dry Granulation<br />
g) Melt Granulation<br />
h) Spray Dry<strong>in</strong>g<br />
i) Mould<strong>in</strong>g<br />
j) Freeze Dry<strong>in</strong>g<br />
a) Direct compression<br />
Conventional equipment, commonly available excipients and a<br />
limited number <strong>of</strong> process<strong>in</strong>g steps are <strong>in</strong>volved <strong>in</strong> direct<br />
compression. This technique can now be applied for preparation <strong>of</strong><br />
ODT, because <strong>of</strong> <strong>the</strong> availability <strong>of</strong> improved excipients especially<br />
super dis<strong>in</strong>tegrants and sugar based excipients.<br />
The <strong>in</strong>troduction <strong>of</strong> superdis<strong>in</strong>tegrants has <strong>in</strong>creased <strong>the</strong> popularity<br />
<strong>of</strong> this technology9. Below a critical level <strong>of</strong> dis<strong>in</strong>tegrant<br />
concentration, tablet dis<strong>in</strong>tegration time becomes <strong>in</strong>versely<br />
proportional to dis<strong>in</strong>tegrant concentration.<br />
However, above <strong>the</strong> critical concentration level <strong>of</strong> dis<strong>in</strong>tegrant,<br />
dis<strong>in</strong>tegration time rema<strong>in</strong>s approximately constant or <strong>the</strong> decrease<br />
is <strong>in</strong>significant10. Bi et al. 11 and Watnabe12 used microcrystall<strong>in</strong>e<br />
cellulose (MCC) and low substituted hydroxypropyl cellulose (HPC)<br />
to manufacture ODTs where<strong>in</strong> <strong>the</strong> ratio <strong>of</strong> MCC to HPC varied from<br />
8:2 to 9:1. Ano<strong>the</strong>r approach to manufacture ODTs by direct<br />
compression is <strong>the</strong> use <strong>of</strong> sugar‐based excipients (dextrose, fructose,<br />
isomalt, maltose, mannitol, sorbitol, xylitol) which display high<br />
aqueous solubility and sweetness and hence, imparts taste mask<strong>in</strong>g<br />
and a pleas<strong>in</strong>g mouth feel.<br />
b) Sublimation<br />
The presence <strong>of</strong> highly porous structure <strong>in</strong> <strong>the</strong> tablet is <strong>the</strong> key<br />
factor for rapid dis<strong>in</strong>tegration <strong>of</strong> ODT. When volatile materials are<br />
compressed <strong>in</strong>to <strong>tablets</strong> us<strong>in</strong>g <strong>the</strong> conventional method, <strong>the</strong>y can be<br />
removed via sublimation, result<strong>in</strong>g <strong>in</strong> highly porous structures. The<br />
volatile materials <strong>in</strong>clude urea, ammonium carbonate, ammonium<br />
bicarbonate, hexa methylene tetram<strong>in</strong>e, and camphor. He<strong>in</strong>emann13 disclosed a process to prepare porous <strong>tablets</strong> by sublimation. The<br />
mixtures <strong>of</strong> volatile adjuvents were made <strong>in</strong>to <strong>tablets</strong> and<br />
subsequently heated. The volatile <strong>in</strong>gredient while leav<strong>in</strong>g <strong>the</strong> core<br />
<strong>of</strong> tablet makes pores <strong>in</strong>to it.<br />
c) Humidity treatment<br />
The mechanical strength <strong>of</strong> some <strong>tablets</strong> <strong>in</strong>creased substantially<br />
after moisture treatment, compared with <strong>the</strong> <strong>tablets</strong> before <strong>the</strong><br />
treatment. The <strong>in</strong>crease is known to be due to <strong>the</strong> formation <strong>of</strong> liquid<br />
bridges <strong>in</strong> <strong>the</strong> presence <strong>of</strong> moisture and <strong>the</strong>n formation <strong>of</strong> solid<br />
bridges after dry<strong>in</strong>g. When an amorphous sugar is treated to go<br />
through <strong>the</strong> humidification and dry<strong>in</strong>g process, it changes to a<br />
crystall<strong>in</strong>e state. This change <strong>in</strong>creases <strong>the</strong> tablet strength<br />
substantially14,15. In a patent by Mizumoto et al 15 a drug, a sugar, and an amorphous<br />
sugar capable <strong>of</strong> transform<strong>in</strong>g from amorphous to crystall<strong>in</strong>e state<br />
were mixed and compressed <strong>in</strong>to <strong>tablets</strong>. After <strong>the</strong> <strong>tablets</strong> were<br />
formed, <strong>the</strong>y were humidified and dried. The “amorphous sugar” are<br />
those that can form an amorphous state by spray dry<strong>in</strong>g, freeze<br />
dry<strong>in</strong>g, or o<strong>the</strong>r granulation methods. These amorphous sugars<br />
<strong>in</strong>clude glucose, lactose, maltose, sorbitol, trehalose, lactilol, and<br />
fructose. The relative humidity is determ<strong>in</strong>ed by <strong>the</strong> apparent<br />
critical relative humidity <strong>of</strong> <strong>the</strong> mixture <strong>of</strong> a drug and an amorphous<br />
sugar. A relative humidity greater than or equal to <strong>the</strong> critical<br />
relative humidity <strong>of</strong> this mixture is chosen for <strong>the</strong> humidity<br />
condition. The advantage <strong>of</strong> us<strong>in</strong>g amorphous sugar is that <strong>the</strong>y have<br />
low critical relative humidity, so that <strong>the</strong>y can absorb water even at<br />
low moisture levels. If a high humidity condition is used, <strong>tablets</strong> may<br />
adhere toge<strong>the</strong>r, caus<strong>in</strong>g manufactur<strong>in</strong>g problems. Ano<strong>the</strong>r<br />
advantage <strong>of</strong> us<strong>in</strong>g amorphous sugar is that transformation <strong>of</strong> <strong>the</strong><br />
39
amorphous state to <strong>the</strong> crystall<strong>in</strong>e state is irreversible. The sugars <strong>in</strong><br />
crystall<strong>in</strong>e state have a high critical moisture po<strong>in</strong>t, so <strong>the</strong><br />
streng<strong>the</strong>ned <strong>tablets</strong> are less susceptible to moisture.<br />
d) S<strong>in</strong>ter<strong>in</strong>g<br />
When <strong>the</strong>rmal energy is applied to a powder compact, <strong>the</strong> compact<br />
is densified and <strong>the</strong> average gra<strong>in</strong> size <strong>in</strong>creases. The basic<br />
phenomena occurr<strong>in</strong>g dur<strong>in</strong>g this process, called s<strong>in</strong>ter<strong>in</strong>g, are<br />
densification and gra<strong>in</strong> growth. Lagoviyer et al16 disclosed a process<br />
that tablet strength can be <strong>in</strong>creased by s<strong>in</strong>ter<strong>in</strong>g <strong>the</strong> tablet<br />
components at high temperatures and <strong>the</strong>n resolidify<strong>in</strong>g <strong>the</strong>m at<br />
lower temperatures. The components <strong>in</strong> this <strong>formulation</strong> <strong>in</strong>clude<br />
bulk agents, structure agents, solvent, and b<strong>in</strong>d<strong>in</strong>g agents. A bulk<br />
agent <strong>in</strong> this <strong>formulation</strong> is used to provide bulk volume to <strong>the</strong><br />
overall tablet, and suitable agents <strong>in</strong>clude carbohydrates, calcium<br />
carbonate, and magnesium carbonate. The suitable structure agents<br />
should provide a porous support structure to allow quick dissolution<br />
<strong>of</strong> <strong>the</strong> <strong>tablets</strong> <strong>in</strong> <strong>the</strong> mouth. Solvents can be chosen from water, ethyl<br />
alcohol, isopropyl alcohol, or a mixture <strong>the</strong>re<strong>of</strong>. B<strong>in</strong>ders are water<br />
soluble polymers such as polyethylene glycol (PEG), with a<br />
molecular weight <strong>of</strong> approximately 1000 to 1,000,000. All <strong>the</strong><br />
<strong>in</strong>gredients dissolved <strong>in</strong>to solvent and spray dried <strong>in</strong>to granules. The<br />
granules are <strong>the</strong>n lightly compressed to form <strong>tablets</strong>. These <strong>tablets</strong><br />
are heated for a sufficient time and temperature to allow <strong>the</strong> b<strong>in</strong>d<strong>in</strong>g<br />
agent to melt. The heat<strong>in</strong>g step is <strong>in</strong>tended to melt <strong>the</strong> b<strong>in</strong>d<strong>in</strong>g agent<br />
to create <strong>in</strong>tra‐tablet bonds and help weld <strong>the</strong> product shape<br />
toge<strong>the</strong>r. Typically, a laboratory oven is set at around 50‐1000C. The<br />
heat<strong>in</strong>g time ranges from 3 to 45 m<strong>in</strong>utes. The b<strong>in</strong>d<strong>in</strong>g agents are<br />
resolidified as <strong>the</strong> temperature is reduced to ambient temperature.<br />
The dis<strong>in</strong>tegration time is generally with<strong>in</strong> 3‐60 seconds.<br />
e) Wet granulation<br />
Bonadeo et al17 described a process <strong>of</strong> produc<strong>in</strong>g ODTs by wet<br />
granulation <strong>in</strong> a fluidized bed. The <strong>formulation</strong> <strong>in</strong>cludes polyalcohols<br />
(e.g., mannitol, xylitol, sorbitol, maltilol, erythritol, and lactilol), 1‐<br />
30% <strong>of</strong> an edible acid, and an active <strong>in</strong>gredient as <strong>the</strong> dry mixture.<br />
This mixture was wet granulated with an aqueous solution <strong>of</strong> a<br />
water‐soluble or water‐dispersible polymer (e.g, polyethylene<br />
glycols, carrageenam, and ethyl cellulose), which consisted <strong>of</strong> 1‐10%<br />
<strong>of</strong> <strong>the</strong> f<strong>in</strong>al weight <strong>of</strong> <strong>the</strong> granule <strong>in</strong> a fluid bed. Granules with high<br />
porosity and low apparent density were obta<strong>in</strong>ed, and <strong>the</strong> <strong>tablets</strong><br />
made by such granules had rapid dis<strong>in</strong>tegration times rang<strong>in</strong>g from<br />
3 to 30 seconds <strong>in</strong> <strong>the</strong> saliva.<br />
f) Dry Granulation<br />
Eoga and Valia18 disclosed a method <strong>of</strong> preparation <strong>of</strong> ODTs by dry<br />
granulation. Low‐density alkali earth metal salts or water‐soluble<br />
carbohydrates were precompacted, and <strong>the</strong> result<strong>in</strong>g granules were<br />
compressed <strong>in</strong>to <strong>tablets</strong> that could dissolve fast. In this process, a<br />
powdered material with a density <strong>of</strong> 0.2 to 0.55 gm/ml was<br />
precompacted to <strong>in</strong>crease <strong>the</strong> density to 0.4 to 0.75 g/ml by apply<strong>in</strong>g<br />
pressure rang<strong>in</strong>g from 1 to 9 kN/cm. The result<strong>in</strong>g granules were<br />
compressed <strong>in</strong>to <strong>tablets</strong>.<br />
g) Melt granulation<br />
Abdelbery et al19 described a new approach <strong>of</strong> prepar<strong>in</strong>g ODTs with<br />
sufficient mechanical strength, <strong>in</strong>volv<strong>in</strong>g <strong>the</strong> use <strong>of</strong> a hydrophilic<br />
waxy b<strong>in</strong>der(SuperpolystateR, PEG‐6‐stearate) by melt granulation<br />
or wet granulation. In case <strong>of</strong> melt granulation granules were<br />
prepared <strong>in</strong> a high speed blade mixer at 40‐440C, accord<strong>in</strong>g to <strong>the</strong><br />
conventional hot‐melt procedure. For wet granulation, an oil‐<strong>in</strong>‐<br />
water emulsion <strong>of</strong> SuperpolystateR was used as <strong>the</strong> granulat<strong>in</strong>g<br />
agent. Then, granules were blended with croscarmellose, aspartame,<br />
and magnesium stearate and compressed <strong>in</strong>to <strong>tablets</strong>. The melt<br />
granulation ODTs had better hardness results than <strong>the</strong> wet<br />
granulation ODTs. The dis<strong>in</strong>tegration times <strong>of</strong> melt granulation<br />
<strong>tablets</strong>, however, was more than one m<strong>in</strong>utes.<br />
h) Spray dry<strong>in</strong>g<br />
Spray dry<strong>in</strong>g technique produces highly porous and f<strong>in</strong>e powders as<br />
<strong>the</strong> process<strong>in</strong>g solvent is evaporated dur<strong>in</strong>g this process. Allen et al20 have used spray‐dry<strong>in</strong>g for <strong>the</strong> production <strong>of</strong> ODTs. The<br />
<strong>formulation</strong>s conta<strong>in</strong>ed hydrolyzed and nonhydrolyzed gelat<strong>in</strong>e<br />
Giri et al.<br />
Int J Pharmacy and Pharm Sci, Vol 2, Issue 3, 3842<br />
(same net charge) as a support<strong>in</strong>g agent for <strong>the</strong> matrix, mannitol as a<br />
bulk<strong>in</strong>g agent and sodium starch glycolate/croscarmellose as a<br />
dis<strong>in</strong>tegrant.<br />
To ma<strong>in</strong>ta<strong>in</strong> <strong>the</strong> net charges <strong>of</strong> <strong>the</strong> gelat<strong>in</strong>e, an acidify<strong>in</strong>g or<br />
alkal<strong>in</strong>iz<strong>in</strong>g agent was <strong>in</strong>cluded. The reason to use gelat<strong>in</strong>e<br />
components <strong>of</strong> <strong>the</strong> same charge was that molecules would repel<br />
each o<strong>the</strong>r even after spray dry<strong>in</strong>g, so that <strong>the</strong> porous particles could<br />
be formed. A m<strong>in</strong>imal amount <strong>of</strong> an effervescent agent was optimally<br />
<strong>in</strong>cluded to fur<strong>the</strong>r accelerate <strong>the</strong> dissolution rate. The suspension <strong>of</strong><br />
above excipients was spray‐dried to yield a porous powder which<br />
was compressed <strong>in</strong>to <strong>tablets</strong>. Tablets manufactured by this method<br />
dis<strong>in</strong>tegrated <strong>in</strong> less than 20 seconds <strong>in</strong> aqueous medium.<br />
i) Mould<strong>in</strong>g<br />
Moulded <strong>tablets</strong> conta<strong>in</strong> water soluble <strong>in</strong>gredients due to which <strong>the</strong><br />
<strong>tablets</strong> dissolve completely and rapidly. Mould<strong>in</strong>g process is <strong>of</strong> two<br />
type’s i.e. solvent method and heat method. Solvent method <strong>in</strong>volves<br />
moisten<strong>in</strong>g <strong>the</strong> powder blend with a hydroalcoholic solvent followed<br />
by compression at low pressure <strong>in</strong> moulded plates to form a wetted<br />
mass. The solvent is <strong>the</strong>n removed by air dry<strong>in</strong>g. The heat mould<strong>in</strong>g<br />
process <strong>in</strong>volves preparation <strong>of</strong> a suspension that conta<strong>in</strong>s a drug,<br />
agar and sugar (e.g. mannitol or lactose) and pour<strong>in</strong>g <strong>the</strong> suspension<br />
<strong>in</strong> <strong>the</strong> blister packag<strong>in</strong>g wells, solidify<strong>in</strong>g <strong>the</strong> agar at <strong>the</strong> room<br />
temperature to form a jelly and dry<strong>in</strong>g at 300C under vacuum. Pebley<br />
et al21 evaporated <strong>the</strong> frozen mixture conta<strong>in</strong><strong>in</strong>g a gum(e.g. acacia,<br />
carageenam, guar, tragacanth or xanthan), a carbohydrate (e.g.<br />
dextrose, lactose, maltose, mannitol or maltodextr<strong>in</strong>) and solvent <strong>in</strong><br />
a tablet‐shaped mould to design a ODT with a dis<strong>in</strong>tegration time <strong>of</strong><br />
about 20‐60 seconds.<br />
j) Freeze dry<strong>in</strong>g<br />
In freeze dry<strong>in</strong>g process, <strong>the</strong> water is sublimed from <strong>the</strong> product<br />
after it is frozen. The active drug is dissolved or dispersed <strong>in</strong> an<br />
aqueous solution <strong>of</strong> a carrier/polymer. The mixture is poured <strong>in</strong> <strong>the</strong><br />
walls <strong>of</strong> <strong>the</strong> preformed blister packs. The trays hold<strong>in</strong>g <strong>the</strong> blister<br />
packs are passed through liquid nitrogen freez<strong>in</strong>g tunnel to freeze<br />
<strong>the</strong> drug solution or dispersion. Then <strong>the</strong> frozen blister packs are<br />
placed <strong>in</strong> refrigerated cab<strong>in</strong>ets to cont<strong>in</strong>ue <strong>the</strong> freeze dry<strong>in</strong>g. After<br />
freeze dry<strong>in</strong>g <strong>the</strong> alum<strong>in</strong>ium foil back<strong>in</strong>g is applied on a blister<br />
seal<strong>in</strong>g mach<strong>in</strong>e. Jaccend and Leyder8 used freeze dry<strong>in</strong>g to develop<br />
an oral <strong>formulation</strong> <strong>of</strong> several drugs such as spiranolactone and<br />
trolendomyc<strong>in</strong>. Corveleyn and Remon5,22 studied various<br />
<strong>formulation</strong>s and process parameters by us<strong>in</strong>g hydrochlorothiazide<br />
as a model drug.<br />
PATENTED TECHNOLOGIES FOR ODTs<br />
Zydis technology<br />
Zydis is a unique freeze dried oral solid dosage form that can be<br />
adm<strong>in</strong>istered without water and it dissolves <strong>in</strong>stantly on <strong>the</strong> tongue<br />
<strong>in</strong> less than 3 seconds.<br />
The drug is physically trapped <strong>in</strong> a water soluble matrix, and <strong>the</strong>n<br />
freeze dried to produce a product that rapidly dissolves. The matrix<br />
usually conta<strong>in</strong> excipients like polymers (e.g., gelat<strong>in</strong>e, alg<strong>in</strong>ates, and<br />
dextr<strong>in</strong>) to provide strength and rigidity to <strong>tablets</strong>;<br />
polysaccharides(e.g., mannitol and sorbitol) to impart crystall<strong>in</strong>ity<br />
and hardness to <strong>the</strong> matrix and to improve palatability; collapse<br />
protectants(e.g, glyc<strong>in</strong>) to prevent <strong>the</strong> product from shr<strong>in</strong>k<strong>in</strong>g <strong>in</strong> its<br />
packag<strong>in</strong>g dur<strong>in</strong>g manufactur<strong>in</strong>g or storage; flocculat<strong>in</strong>g agents(e.g,<br />
xanthan gum and acacia) to provide uniform dispersion <strong>of</strong> drug<br />
particles; preservatives(e.g., parabens) to prevent microbial growth;<br />
permeation enhancers(e.g., sodium lauryl sulphate) to improve<br />
transmucosal permeability; pH adjusters(e.g, citric acid) to optimize<br />
chemical stability; flavours and sweetners to improve patient<br />
compliance and water to ensure formation <strong>of</strong> porous units.<br />
Thirteen products are currently available based on zydis<br />
technology 23. In US, <strong>the</strong> zydis products available are Clarit<strong>in</strong> Reditab,<br />
Dimetapp Quick Dissolve, Feldene Melt, Maxalt‐MLT, Pepcid RPD,<br />
Z<strong>of</strong>ran ODT, and Zyprexa Zydis. In <strong>the</strong> worldwide market, zydis<br />
<strong>formulation</strong>s are also available for oxazepam, lorazepam,<br />
loperamide, and enalepril 24.<br />
40
Orasolv technology<br />
CIMA labs have developed orasolv technology25. It uses an<br />
effervescent agent that releases gas upon contact with water.<br />
Effervescent agent usually <strong>in</strong>cludes an acid source and a carbonate<br />
source. The acid sources <strong>in</strong>clude citric acid, tartaric acid, malic acid,<br />
fumaric acid, adipic acid, and succ<strong>in</strong>ic acids. The carbonate sources<br />
<strong>in</strong>clude sodium bicarbonate, sodium carbonate, potassium<br />
bicarbonate, and potassium carbonate. Tablets are prepared by<br />
direct compression at low compression force <strong>in</strong> order to m<strong>in</strong>imize<br />
oral dis<strong>in</strong>tegration time. The active medicaments are taste masked<br />
and dispersed <strong>in</strong> saliva due to <strong>the</strong> action <strong>of</strong> effervescent agents. It<br />
provides <strong>the</strong> pleasant sensation <strong>in</strong> mouth <strong>of</strong> <strong>the</strong> patient.<br />
Durasolv technology<br />
Durasolv26 is <strong>the</strong> patented technology <strong>of</strong> CIMA labs. The <strong>tablets</strong> made<br />
by this technology consist <strong>of</strong> a drug, fillers and a lubricant. Tablets<br />
are prepared by direct compression technique us<strong>in</strong>g conventional<br />
tablet<strong>in</strong>g equipment and have good rigidity. These can be packed<br />
<strong>in</strong>to conventional packag<strong>in</strong>g systems like blisters. Durasolv is an<br />
appropriate technology for products requir<strong>in</strong>g low amounts <strong>of</strong> active<br />
<strong>in</strong>gredients.<br />
Wowtab technology<br />
Wowtab technology27 is patented by Yamanouchi pharmaceutical<br />
company. Wow means “without water”. In this process, comb<strong>in</strong>ation<br />
<strong>of</strong> low mouldability saccharides and high mouldability saccharides<br />
are used to obta<strong>in</strong> a rapidly melt<strong>in</strong>g strong tablet. Various low‐<br />
mouldability saccharides are lactose, mannitol, glucose, sucrose and<br />
xylitol. Also various high‐mouldability saccharides are maltose,<br />
maltilol, and sorbitol. A tablet prepared with low‐mouldability or<br />
high‐mouldability saccharides alone does not achieve adequate<br />
hardness and quick dis<strong>in</strong>tegration simultaneously. However if both<br />
<strong>the</strong> saccharides physically mixed before compression quick<br />
dis<strong>in</strong>tegration cannot be obta<strong>in</strong>ed. For this reason <strong>the</strong> active<br />
<strong>in</strong>gredient is mixed with a low‐mouldability saccharide and<br />
granulated with a high‐mouldability saccharide and compressed <strong>in</strong>to<br />
tablet.<br />
Flashtab technology<br />
Flashtab technology28 is patented by Prographarm laboratories.<br />
Tablets prepared by this system consist <strong>of</strong> an active <strong>in</strong>gredient <strong>in</strong> <strong>the</strong><br />
form <strong>of</strong> microcrystals. Drug micro‐granules may be prepared by<br />
us<strong>in</strong>g <strong>the</strong> conventional techniques like coacervation,<br />
microencapsulation, and extrusion‐spheronization. All <strong>the</strong>se<br />
processes utilized conventional tablet<strong>in</strong>g technology.<br />
Pharmaburst technology<br />
Pharmaburst technology is patented by SPI pharma. Tablet<br />
manufactured by this process <strong>in</strong>volves a dry blend <strong>of</strong> a drug, flavour,<br />
and lubricant followed by compression <strong>in</strong>to <strong>tablets</strong>; which dissolve<br />
with<strong>in</strong> 30‐40 seconds. Tablets manufactured by this method hav<strong>in</strong>g<br />
sufficient strength so <strong>the</strong>y can be packed <strong>in</strong> blister packs and<br />
bottles29. Shearform technology<br />
The shearform technology27,28 is based on preparation <strong>of</strong> floss that is<br />
also known as ‘shearform matrix’, which is produced by subject<strong>in</strong>g a<br />
feed stock conta<strong>in</strong><strong>in</strong>g a sugar carrier by flash heat process<strong>in</strong>g. The<br />
<strong>tablets</strong> manufactured by this process are highly porous <strong>in</strong> nature<br />
and <strong>of</strong>fer very pleasant mouth feel due to rapid solubilisation <strong>of</strong><br />
sugars <strong>in</strong> presence <strong>of</strong> saliva. At first sucrose <strong>in</strong> comb<strong>in</strong>ation with<br />
mannitol/dextrose and surfactant is blended to form <strong>the</strong> floss mix.<br />
The surfactant acts as a crystallization enhancer <strong>in</strong> ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g <strong>the</strong><br />
structural <strong>in</strong>tegrity <strong>of</strong> <strong>the</strong> floss fibres and also helps <strong>in</strong> <strong>the</strong><br />
conversion <strong>of</strong> amorphous sugar <strong>in</strong>to crystall<strong>in</strong>e form from an outer<br />
portion <strong>of</strong> amorphous sugar mass. Subsequently <strong>in</strong> <strong>the</strong> flash heat<br />
process, <strong>the</strong> heat <strong>in</strong>duces an <strong>in</strong>ternal flow condition <strong>of</strong> <strong>the</strong> carrier<br />
material. This is followed by its exit through <strong>the</strong> sp<strong>in</strong>n<strong>in</strong>g head that<br />
fl<strong>in</strong>gs <strong>the</strong> floss under centrifugal force and draws <strong>in</strong>to long and th<strong>in</strong><br />
floss fibres, which are usually amorphous <strong>in</strong> nature. The floss so<br />
produced is fur<strong>the</strong>r chopped(conversion <strong>of</strong> fibres <strong>in</strong>to smaller<br />
particles <strong>in</strong> a high shear mixer granulator) and recrystallized<br />
Giri et al.<br />
Int J Pharmacy and Pharm Sci, Vol 2, Issue 3, 3842<br />
through an ethanol treatment(1%) which is sprayed onto <strong>the</strong> floss<br />
and subsequently evaporated to impart improved flow and cohesive<br />
properties to <strong>the</strong> floss. The recrystallized matrix is <strong>the</strong>n blended<br />
with <strong>the</strong> drug along with o<strong>the</strong>r excipients and compressed <strong>in</strong>to<br />
<strong>tablets</strong>. In order to improve <strong>the</strong> mechanical strength <strong>the</strong> <strong>tablets</strong> are<br />
exposed to elevated temperature and high humidity (400C and 85%<br />
RH for 15 m<strong>in</strong>utes).<br />
Ceform Technology<br />
In ceform technology29 microspheres conta<strong>in</strong><strong>in</strong>g active drug<br />
<strong>in</strong>gredient are prepared. The essence <strong>of</strong> ceform microsphere<br />
manufactur<strong>in</strong>g process <strong>in</strong>volves plac<strong>in</strong>g a dry powder, conta<strong>in</strong><strong>in</strong>g<br />
pure drug and excipients <strong>in</strong>to a rapidly sp<strong>in</strong>n<strong>in</strong>g mach<strong>in</strong>e. The<br />
centrifugal force <strong>of</strong> <strong>the</strong> rotat<strong>in</strong>g head <strong>of</strong> ceform mach<strong>in</strong>e throws <strong>the</strong><br />
dry drug blend at high speed through small heated open<strong>in</strong>gs. The<br />
carefully controlled temperature <strong>of</strong> <strong>the</strong> resultant microburst <strong>of</strong> heat<br />
liquefies <strong>the</strong> drug blend to form a sphere without adversely affect<strong>in</strong>g<br />
drug stability. The microspheres are <strong>the</strong>n blended and/or<br />
compressed <strong>in</strong>to <strong>the</strong> preselected oral dosage format.<br />
Ziplet Technology<br />
In ziplet technology water <strong>in</strong>soluble drugs or drugs as coated<br />
microparticles are used. The addition <strong>of</strong> a suitable amount <strong>of</strong> a<br />
water‐<strong>in</strong>soluble <strong>in</strong>organic excipients comb<strong>in</strong>ed with dis<strong>in</strong>tegrants<br />
imparted an excellent physical resistance to <strong>the</strong> ODT and<br />
simultaneously ma<strong>in</strong>ta<strong>in</strong>ed optimal dis<strong>in</strong>tegration30. The use <strong>of</strong><br />
water‐<strong>in</strong>soluble <strong>in</strong>organic excipients <strong>of</strong>fer better enhancement <strong>of</strong><br />
dis<strong>in</strong>tegration <strong>in</strong> comparison to <strong>the</strong> most commonly used water‐<br />
soluble sugars or salts. Tablets primarily <strong>of</strong> water soluble<br />
components <strong>of</strong>ten tend to dissolve ra<strong>the</strong>r than dis<strong>in</strong>tegrate and<br />
concentrated viscous solution is formed which reduces <strong>the</strong> rate <strong>of</strong><br />
water diffusion <strong>in</strong>to <strong>the</strong> tablet core9. Oraquick technology<br />
Oraquick is a patented taste mask<strong>in</strong>g technology pioneered by KV<br />
pharmaceuticals. It supports <strong>the</strong> <strong>in</strong>corporation <strong>of</strong> taste mask<strong>in</strong>g<br />
technology. The taste mask<strong>in</strong>g process does not utilize solvents <strong>of</strong><br />
any k<strong>in</strong>d and <strong>the</strong>refore leads to faster and efficient production.<br />
Tablets with sufficient mechanical strength without disrupt<strong>in</strong>g taste<br />
mask<strong>in</strong>g are obta<strong>in</strong>ed after compression. This technology had also<br />
been utilized <strong>in</strong> <strong>the</strong> <strong>development</strong> <strong>of</strong> ODTs conta<strong>in</strong><strong>in</strong>g hyoscyam<strong>in</strong>e<br />
sulphate which is a bitter tast<strong>in</strong>g drug31. Frosta Technology<br />
This technology is patented by Ak<strong>in</strong>a. Frosta technology utilizes <strong>the</strong><br />
core concept <strong>of</strong> formulat<strong>in</strong>g plastic granules and compress<strong>in</strong>g at low<br />
pressure to produce strong <strong>tablets</strong> with high porosity. The process<br />
<strong>in</strong>volves mix<strong>in</strong>g <strong>the</strong> porous plastic material with water penetration<br />
enhancer and followed by granulat<strong>in</strong>g with b<strong>in</strong>der. The technology<br />
can be used for almost any drugs <strong>in</strong>clud<strong>in</strong>g aspir<strong>in</strong>, loratid<strong>in</strong>e,<br />
caffe<strong>in</strong>e, and folic acid, vitam<strong>in</strong>s and dietary supplements. Melt<strong>in</strong>g<br />
time varies from several seconds to about 10 seconds depend<strong>in</strong>g on<br />
<strong>the</strong> <strong>formulation</strong>.<br />
Nanocrystal technology<br />
Nanocrystal technology is patented by Elan, K<strong>in</strong>g <strong>of</strong> Prussia.<br />
Nanocrystal ODT technology provides for pharmacok<strong>in</strong>etic benefits<br />
<strong>of</strong> orally adm<strong>in</strong>istered nanoparticles(less than 2 microns) <strong>in</strong> <strong>the</strong><br />
form <strong>of</strong> a rapidly dis<strong>in</strong>tegrat<strong>in</strong>g tablet matrix. Nanocrystal<br />
technology <strong>in</strong>cludes lyophilisation <strong>of</strong> colloidal dispersions <strong>of</strong> drug<br />
substances and water soluble <strong>in</strong>gredients filled <strong>in</strong>to blister pockets.<br />
This method avoids manufactur<strong>in</strong>g process such as granulation,<br />
blend<strong>in</strong>g and tablett<strong>in</strong>g which is more advantageous for highly<br />
potent hazardous drug.<br />
CONCLUSION<br />
The techniques and technologies described <strong>in</strong> this article represent<br />
how recent advances <strong>in</strong> <strong>formulation</strong> <strong>development</strong> and process<strong>in</strong>g<br />
technologies make <strong>the</strong> efforts to achieve <strong>orodispersible</strong> <strong>tablets</strong>.<br />
ODTs have better patient acceptance and compliance and may <strong>of</strong>fer<br />
improved biopharmaceutical properties, improved efficacy, and<br />
41
etter safety compared with conventional oral dosage forms. To<br />
provide <strong>the</strong> patients with <strong>the</strong> most conventional mode <strong>of</strong><br />
adm<strong>in</strong>istration, <strong>the</strong>re was a need to develop rapidly dis<strong>in</strong>tegrat<strong>in</strong>g<br />
dosage form, particularly one that dis<strong>in</strong>tegrates and<br />
dissolve/disperse <strong>in</strong> saliva and can be adm<strong>in</strong>istered without need <strong>of</strong><br />
water. A number <strong>of</strong> ODT products based on various technologies are<br />
now commercially available <strong>in</strong> <strong>the</strong> <strong>in</strong>ternational market. The basic<br />
approach followed by all <strong>the</strong> available ODTs technologies is to<br />
maximize <strong>the</strong> porous structure <strong>of</strong> tablet matrix to achieve rapid<br />
tablet dis<strong>in</strong>tegration <strong>in</strong> <strong>the</strong> oral cavity along with good taste‐mask<strong>in</strong>g<br />
properties and excellent mechanical strength.<br />
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