Advance granulation technology (Rapid release granulation technology)

1. RAPID RELEASE
GRANULATION TECHNOLOGY
Presented By:
Hasnat Tariq
GULAB DEVI INSTITUTE OF PHARMACY (GDIP)

2.  The process in which primary powder particle are made to adhere to form large
multiparticle entitles or agglomerates is known as Granulation.

3.  To control the rate of drug release
 To improve flow property and compression characteristics.
 To increase density of granules
 To make hydrophobic surfaces more hydrophilic
 To prevent the segregation of particles.

4. Definition :
It is a technique in which all those parameters/processes/variables which
cause the rapid release of drug are applied in the preparation of granules
Q:Why we need rapid release granulation?
 It is for the class of compound where absorption is highly dependent on
dissolution of drug in gastrointestinal tract termed as Class II compounds
under the Biopharmaceutics Classification system.
 These compounds were abandoned during pre-formulation stage because
they did not exhibit sufficient solubility in the aqueous environment,
implying reduced bioavailability upon administration and the inability to
attain the necessary drug levels in blood for therapeutic effect.

5. Biopharmaceutics Classification Scheme
Class Solubility Permeability
I High↑ High↑
II Low↓ High↑
III High↑ Low↓
IV Low↓ Low↓

6.  The focus of the current presentation is to examine some of the
dosage-form related factors which can be controlled from the
formulator’s perspective, to enhance the dissolution of the bioactive
compounds in order to increase the bioavailability of poorly water-
soluble compounds through the granulation process, which is
making granules to be filled into capsules or tableted.
Solubility is important because for a drug to be absorb and be
available in systemic circulation it must have adequate solubility.
To check solubility we have to check its dissolution because
dissolution is a benchmark to test solubility.

8. A.FORMULATION
RELATED FACTORS

9.  Drug
I. Free acid, free base
II. Particle size
III. Amorphous state
IV. Polymorph and solvates
V. Solution based micronization
 Additives
I. Solubilizing Agent
II. Effervescent Agent
III. Hydrophilic Agent
IV. Lubricant
V. Surface Active Agent
VI. Superdisintegrant

10. 1. Drug related factor
affecting Rapid Release

11.  The use of the appropriate form of drug prior to granulation is of utmost importance
to ensure the production of rapid release granules.
 Sodium salts of weak acids or Hydrochloride salts of weak bases can cause marked
increase in aqueous solubility when compared to the corresponding free acids or
bases. This is attributed to an increase in interactions between drug and water, giving
rise to a greater degree of ionic dissociation of the drug when it dissolves in water.
Examples:
 An example of this effect is the aqueous solubilities of Salicylic Acid and its sodium salt,
which are 1:550 and 1:1, respectively
 Diclofenac, is the drug in its free acid form, while Diclofenac Sodium and Diclofenac
Potassium the salts of the drug.

12. According to Noyes Whitney equation
𝒅𝑪
𝒅𝒕
=
𝑨𝑫(𝑪𝑺 − 𝑪)
𝒉
Where;
 dC/dt is the dissolution rate,
 A is the surface area of particles
 D is the diffusion coefficient of the compound
 Cs is concentration of the drug (equal to the solubility of the drug) in the stagnant layer
 C is the concentration of drug in bulk solvent
 h is thickness of stagnant layer.

13.  The most common approach for improving the dissolution rate (dC/dt) of drug for rapid
release granules is to increase the surface area (A) available for dissolution and this is often
achieved by employing finely divided particles. Size reduction has also been shown to decrease
the stagnant layer (h) of sparingly soluble drugs.
 As a particle becomes smaller, the surface area to volume ratio increases. The larger surface
area allows greater interaction with the solvent which causes an increase in solubility
Example: Griseofulvin represents a classic example of a drug where improvement in rate
of absorption can be brought about by an increase in dissolution rate due to the increase in
surface area by size reduction. It is demonstrated that
0.5 g of micronized griseofulvin = 1.0 g of the un-micronized form (produced the same
serum level )

14.  Amorphous form is the form where the molecules are arranged in a
random manner.
 Drug solubility is usually higher when the drug exists in the amorphous
form compared to the crystalline form because the process of drug
solubility involves breaking the intermolecular bonds that form the crystal
lattice. Thus, the order of dissolution and hence absorption for different
solid dosage forms is:
Amorphous > Meta-Stable > Stable.
Example:
 Such drug represents the greater solubility. E.g. Novobiocin and Cefuroxime

15.  Polymorphs are substances having same chemical structure but different
physical properties, for e.g. solubility, hardness, density, compression
characteristics.
Example: Carbamazepine polymorph I and IV, which are the respective
anhydrate and dihydrate forms, gave rise to a higher dissolution rate than
polymorphs II and III, which are the anhydride forms.
 Solvates are crystalline forms containing solvent molecules in the crystal
structures. Aqueous solubilities of anhydrous forms are higher than the
hydrate forms.
Example: The Ampicillin Trihydrate less absorbed than its anhydrous form
because of fast dissolution of the anhydrous form of the ampicillin

16.  The poorly soluble drug was dissolved in solvent to make solution and
mixed with a core material, either low-substituted hydroxypropyl cellulose
or partly pregelatinized corn starch.
 The suspension was subsequently spray dried leaving a thin film of fine
drug crystals on the surface of the core materials. The rapid solvent
evaporation prevented the growth of large drug crystals.
 Using disintegrant as the core material further improved drug release
because the swelling of disintegrant would dislodge the thin film of fine
drug crystals from the core for better dissolution, thus effectively dispersing
the fine drug crystals.
Example:
 The poorly soluble drug (Tolbutamide) have improved dissolution after the
application of solution based micronization.

17. 2. Additives effect in a
Formulation for Rapid
Release

18.  An additive is able to improve the dissolution of a poorly water-soluble drug by
forming a water-soluble intermolecular complex. The additive is called
solubilizing agent and it must be present at an optimal concentration to
maximize the solubility of a poorly water-soluble drug.
 One commonly used additive is cyclodextrin.
Example:
 It is showed that complexation and granulation of Piroxicam with b-
cyclodextrin by steam granulation in a single process improved in vitro drug
release

19.  Effervescence is defined as the evolution of bubbles of gas from a liquid
as the result of a chemical reaction. The generation of gas, which is
usually carbon dioxide, is usually achieved by spontaneous chemical
reaction between a soluble acid source and an alkali metal carbonate in
the presence of water.
 Effervescent agents used are Sodium bicarbonate, Citric acid, and
Tartaric acid
Example:
 The bioavailability of Aspirin from effervescence tablet was higher than
conventional or enteric-coated tablets.

20.  In the formulation of rapid release granules, it is always better to employ more
hydrophilic agents so that water penetration into the granules will not be
impeded. These additives aid in wetting the poorly water-soluble drug.
 Hydrophilic agents commonly employed include hydroxylpropylcellulose,
hydropropylmethylcellulose, lactose, microcrystalline cellulose,
polyvinylpyrrolidone, starch.
Example:
 Polyvinylpyrrolidone K30 was able to improve the wetting of Nifedipine
complexed with 2-hydroxypropyl-b-cyclodextrin

21.  Lubricant is employed in a formulation to facilitate the ejection of tablets from
the die. An optimum amount of lubricant must be used for each formulation in
order to optimize the drug dissolution. Excess lubricant interferes with both
disintegration and bioavailability by waterproofing the granules and tablets.
Example:
 It is found that doubling the quantity of Magnesium stearate to be mixed
with Naproxen granules before tableting resulted in a slower drug
dissolution rate due to hydrophobic nature of magnesium stearate.

22.  This additive is capable of forming aggregates called micelles above the critical
micelle concentration. Solubilization results in the increase in the aqueous
solubility of drugs and aids dissolution. It is also able to improve wetting of the
granules. Surfactant can also potentially disrupt the integrity of membranes to
enhance drug absorption.
Examples:
 Sodium lauryl sulfate was employed in the formulation of Ibuprofen tablet
to enhance ibuprofen dissolution.

23.  Superdisintegrants are a specific class of highly effective disintegrants that
have an enhanced ability to rapidly break down the dosage form, resulting in
faster drug release. Some of the common superdisintegrants are Crospovidone,
Croscamellose sodium, and Sodium starch glycolate.
 The addition of disintegrant is to facilitate the breakup of tablet, thus
presenting the micronized drug to the dissolution medium.
Example:
 It is also verified the effectiveness of superdisintegrants in improving the
dissolution of Methylprednisolone and Phenylbutazone

24. B.GRANULATION
RELATED FACTORS

25. The quantity of liquid binder also gives rise to different dissolution
profiles.
Also a low amount used would result in the production of smaller
granules and the resultant tablets formed displayed much faster
dissolution as compared to granules formed using a higher amount
of liquid binder.
Forming larger granules, a higher amount of liquid binder used is
also expected to increase the hardness of granules.
Hard tablets will give rise to poorer dissolution because the tablets
require more time to break

26.  The selection of equipment for wet granulation affects the hardness of the
granules and ultimately influences drug release.
Example:
 Acetaminophen beads made from pan coating displayed higher dissolution
rates as compared to those made from the extrusion/spheronization
method. This was attributed that the disintegration of
extrusion/spheronization beads were denser and less friable due to the
higher energy input during wet massing and thus did not disintegrate during
dissolution.

27.  Increasing the time during wet massing resulted in an increase in bulk density
of the granules( more compacted or densely packed)
 The maximum bulk density value coincided with the minimum dissolution
rate indicating that the dissolution of drug required the diffusion of dissolution
medium into granules via pores to dissolve the drug. Thus, the duration of wet
massing affects the hardness of granules and ultimately, dissolution of the
drug.
Example:
 Wet massing was found to play an important factor in the dissolution rate of
Dyphylline (Xanthine derivative)

28.  The dissolution rate is affected by the type of blending equipment employed,
the duration of blending of granules with disintegrant, glidant, and lubricant.
 It was found that the type of blender affected the distribution of magnesium
stearate and hence, drug dissolution.
Example:
 High-speed blender was employed to mix interactive mixture of Theophylline
with magnesium stearate before tableting. It was found that a 15 min duration
was sufficient to impair theophylline dissolution whereas an impairment of
dissolution was not observed for a lower-speed blender.

29. Manufacturing of Rapid
Release Forms

30.  The term, solid dispersion, refers to a composite solid of one or more drugs in a
water-soluble carrier or matrix prepared by melt (fusion), solvent evaporation
method , or melt–solvent method.
 Solid dispersions have been traditionally employed to enhance the dissolution
rate of drug, with a view to improve bioavailability.
 The common approach to achieve rapid drug dissolution is to use inert but
water-soluble carriers such as polyethylene glycol (PEG) or
polyvinylpyrrolidone (PVP)

31. 1. Melt/fusion method: In this method, the physical mixture of a drug and a water-
soluble carrier are heated directly until the two melts. The melted mixture is then
cooled and solidified rapidly in an ice bath with rigorous stirring. The final solid
mass is then crushed, pulverized, and sieved, which can be compressed into tablets
with the help of tableting agents.
2. Solvent Evaporation Method: Firstly dissolve both the drug and the carrier in a
common solvent and then evaporate the solvent under vacuum to produce a solid
solution.
3. Melt-Solvent Method: This is a hybrid of the two methods discussed. The drug is
dissolved in a suitable organic solvent and the solution is incorporated directly into
a molten carrier. Subsequently, the organic solvent is evaporated off.

32. PROCESSES OF
GRANULATION

33.  First, a mixture of (APIs), Polymer, and effervescent components is prepared. This mixture is
then introduced into a hot melt Extruder where it is heated to a temperature above the
melting point of the binder or matrix material. As the mixture melts, the wet mass is formed,
promoting the agglomeration of the particles.
 The hot, molten mass is subsequently forced through a extruder to create extrudates of the
desired size and are spheronized to form pellets . Cooling is then employed to solidify the
granules/ Pellet.
Examples
 The extruded mixtures always exhibited more rapid release of drug vs. the corresponding
physical mixtures using Carbamazepine as the model drug.
 Used this technique to produce hydrochlorothiazide tablets by directly extruding the melt
into a tablet-shaped cavity. The molded tablet thus formed displayed higher in vitro
dissolution and relative bioavailability in healthy volunteers.

35.  Melt granulation is a process by which powders are agglomerated with the aid
of a binder, in either a molten state or solid state that melts during the process.
 The apparatus of choice is a high-shear mixer, where the temperature of a
powder can be raised above the melting point of a meltable binder by either a
heating jacket or frictional forces generated by the impeller blades.
 Liquid binding is possible by the molten binder, thus melt granulation does not
require the use of solvents.
 The choice of the meltable binder plays an important role in the process. It has
to melt at a temperature of 50–80C. The use of hydrophilic binder that melts at
a low temperature will aid in the rapid release of drug.

36.  The absence of water excludes the wetting and drying phases, making the entire
process less energy- and time-consuming.
 Melt granulation method could be efficiently applied in order to enhance the
stability of moisture sensitive drug and further to improve the poor physical
properties of the drug substance
 Example: Polyethylene glycol 4000 and lactose monohydrate were employed
as the hydrophilic meltable binder and hydrophilic filler, in the formulation of
rapid release Carbamazepine tablets by the melt granulation process
 Drawback of this process is the need of high temperature during the process,
which can cause degradation and/or oxidative instability of the ingredients,
especially of the thermolabile drugs

38. Heater
Temp: 50-80 c

39.  Roll mixing involves the feeding of the powder mix through two rollers. The
powder mass usually includes the drug with one or more water-soluble
carriers. Depending on appropriate processing conditions such as roller
pressure or the use of solvent, the drug may be converted into an amorphous
state.
Example:
 Improved Phenytoin in vitro dissolution release by roll mixing of the drug and
polyvinylpyrrolidone K30, which served as the water-soluble carrier.

41.  Lyophilization, also popularly known as freeze drying, is a process whereby
water is sublimed from frozen solutions, frozen suspensions, or frozen
emulsions; under reduced pressure and temperature, leaving a dry porous
mass of approximately the same shape and size as the original frozen mass.
 Lyophilization essentially consists of three steps, freezing, primary drying, and
secondary drying.
i-Freezing: The materials are cooled until they are frozen.
ii-Primary drying is accomplished under vacuum and slight heating to remove most of
the water by sublimation. The usual range is from -10 °C to 30 °C.
iii-Secondary drying: The last stage is to remove sorbed water, which is carried out
under elevated temperature (50 to 60 °C).

42. The most notable lyophilization process in the pharmaceutical
industry was called Zydis Technology, this technology essentially
involved the filling of blister pocket with a suspension of drug
followed by freeze drying to form a porous tablet of sufficient
strength before sealing of the blister pack. Thus, this technology
could be viewed as a ‘‘Macrogranulation’’, whereby each tablet is
considered a ‘‘Macrogranule.’’
Example
This technique had been successfully used to produce lyophilized
Hydrochlorothiazide tablets displaying better in vitro dissolution
as well as higher bioavailability in human volunteers.

43.  Steam granulation is a derivative of wet granulation technique, which involves
the use of steam instead of traditional liquid binder. Instead of spraying the
liquid binder, steam is emitted into the wet massing chamber.
Advantages
 The processing time is short because less moisture is needed as steam has a
higher diffusion rate into the powder mass, achieving a higher distribution of
the binder.
 It is found that the granules produced were more spherical and had a larger
surface area.
Example: This process successfully produced Diclofenac-polyethylene glycol
4000 rapid release granules whereby polyethylene glycol 4000 acted as the
water-soluble carrier.

45. Handbook of Pharmaceutical Granulation Technology ,Second
Edition ,by Dilip M. Parikh (Page no: 407-423)
https://images.app.goo.gl/RjVdwhVevJE1iu3w7
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