Introduction - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/42012/12/12_chapter 3.p… · the introduction of co-processed microcrystalline cellulose and calcium carbonate

Chapter III: Porous Starch: a Novel Carrier Introduction

Release Modification Designs for Poorly Water Soluble Drugs - 152 -

Introduction

Excipients are all substances contained in a dosage form other than the active substance. Tablets

are the most commonly used dosage form because of the ease of manufacturing; convenience in

administration, accurate dosing and stability compared to oral liquids and direct compression is

the preferred method for the preparation of tablets because of several advantages. In order to

justify the high rise in new drug development and high industrial output demand, new excipients

with purpose satisfying characteristics are the need of the hour. It signifies the synergistic

outcome of the combination of excipient taking their material property into consideration. It also

emphasizes on the particular material properties in terms of physico-mechanical parameters that

are useful to overcome the limitation of existing excipients.

Solvents used for the production of a dosage form but not contained in the final product are

considered to be excipients. Another definition of excipients is, as defined by the International

Pharmaceutical Excipients Council, “Substances, other than the active drug substance or finished

dosage form, which have been appropriately evaluated for safety and are included in a drug

delivery system to either aid the processing of the drug delivery system during its manufacture,

protect, support, enhance stability, bioavailability, or patient acceptability, assist in product

identification, or enhance any other attributes of the overall safety and effectiveness of the drug

delivery system during storage or use’’. Many pharmaceutical scientists have focused their

attention on the production of multifunctional excipients with enhanced performance to meet the

needs of formulation experts in terms of costs of production, enhanced excipient functionality

and quality of tablets.

Tablets and capsules are the most preferred dosage forms of pharmaceutical scientists and

clinicians because they can be accurately dosed and provide good patient compliance, they are

easy for companies to manufacture, and they can be produced at a relatively low cost. Tablets are

manufactured primarily by either granulation compression or direct compression. The latter

involves the compression of a dry blend of powders that comprises drugs and various excipients.

The simplicity and cost effectiveness of the direct-compression process have positioned direct

compression as an attractive alternative to traditional granulation technologies (James, 2006).

Despite many research studies being conducted in the field of drug delivery, none of them have

been able to match the characteristic features and advantages offered by oral unit dosage forms

such as tablets and capsules. With the advent of this form of drug delivery, the subsequent



researches of betterment of this delivery system emerged, which included sophisticated

machinery and superior tabletting aids.

Although simple in terms of unit processes involved, the direct-compression process is highly

influenced by powder characteristics such as flow ability, compressibility, and dilution potential.

Tablets consist of active drugs and excipients, and not one drug substance or excipient possesses

all the desired physical properties required for the development of a robust direct compression

manufacturing process, which can be scaled up from laboratory to production scale smoothly.

Most formulations (70–80%) contain excipients at a higher concentration than the active drug.

Consequently, the excipients contribute significantly to a formulation’s functionality and

processability. In simple terms, the direct-compression process is directly influenced by the

properties of the excipients. The physical properties of excipients that ensure a robust and

successful process are good flowability, good compressibility, low or no moisture sensitivity,

low lubricant sensitivity, and good machineability even in high-speed tableting machinery with

reduced dwell times. The majority of the excipients that are currently available fail to live up to

these functionality requirements, thus creating the opportunity for the development of new high-

functionality excipients.

Search for new excipients

The continued popularity of solid dosage forms, a narrow pipeline of new chemical excipients,

and an increasing preference for the direct-compression process creates a significant opportunity

for the development of high-functionality excipients. The advantage of the existing excipient for

a particular method found to be misappropriating for the other. The development of new

excipients to date has been market driven (i.e., excipients are developed in response to market

demand) rather than marketing-driven (i.e., excipients are developed first and market demand is

created through marketing strategies) and for the past many years, very few single new chemical

excipient has been introduced into the market. The primary reason for this lack of new chemical

excipients is the relatively high cost involved in excipient discovery and development. However,

with the increasing number of new drug moieties with varying physicochemical and stability

properties, there is growing pressure to search for new excipients to achieve the desired set of

functionalities and to obtain compounds having superior properties (hygroscopicity, flow ability,

and compact ability) compared to the individual excipients or their physical mixtures. Hence, at

this juncture development of new excipient by the modification of pre-established ones seems to



be useful and justified one.

Other factors driving the search for new excipients are;

* The growing popularity of the direct-compression process and a demand for an ideal filler–

binder that can substitute two or more excipients

* Tableting machinery’s increasing speed capabilities, which require excipients to maintain

good compressibility and low weight variation even at short dwell times

* Shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose

(MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of

agglomeration.

* The lack of excipients that address the needs of a specific patients such as those with

diabetes, hypertension, and lactose and sorbitol sensitivity

* The ability to modulate the solubility, permeability, or stability of drug molecules

* The growing performance expectations of excipients to address issues such as disintegration,

dissolution, and bioavailability.

Sources of new excipients

Excipients with improved functionality can be obtained by developing new chemical excipients,

new grades of existing materials, and new combinations of existing materials. Any new chemical

excipient being developed as an excipient must undergo various stages of regulatory approval

aimed at addressing issues of safety and toxicity, which is a lengthy and costly process. The high

risk and significant investment involved are not justified in view of the small returns from the

new excipients. Developing new grades of existing excipients (physicochemical) has been the

most successful strategy for the development of new excipients in past three decades, a process

that has been supported by the introduction of better performance grades of excipients such as

pregelatinized starch, croscarmellose, and crospovidone. However, functionality can be

improved only to a certain extent because of the limited range of possible modifications. Many

possible combinations of existing excipients can be used to achieve the desired set of

performance characteristics. However, the development of such combinations is a complex

process because one excipient may interfere with the existing functionality of another excipient.

Development of single-bodied excipient by bringing change in the sub-particle level has gained

importance over the years resulting in co processed excipients. To deal with change of particle’s

physical property at sub-particle level and methodology for development of a new synergistic



modification leads to the development of improved excipient. Processing excipients leads to the

formation of excipient granulates with superior properties compared with physical mixtures of

components or with individual components. They have been developed primarily to address the

issues of flowability, compressibility, and disintegration potential, with filler–binder

combinations being the most commonly tried.

Approaches for development of processed excipients

A much broader platform for the manipulation of excipient functionality is provided by

processing or particle engineering two or more existing excipients. Processing was initially used

by the food industry to improve stability, wettability, and solubility and to enhance the gelling

properties of food ingredients such as co-processed glucomannan and galactomanan. Processing

of excipients in the pharmaceutical industry can be dated back to the late 1980s with

the introduction of co-processed microcrystalline cellulose and calcium carbonate (Dev, 1988),

followed by Cellactose in 1990, which is a co-processed combination of cellulose and lactose. It

involves a thorough understanding of material properties and processing two or more excipients

by methods such as co-spray drying or co-precipitation etc.

Particle engineering as a handy tool

Particle engineering is a broad-based concept that involves the manipulation of particle

parameters such as shape, size, size distribution, and simultaneous minor changes that occur at

the molecular level such as polytypic and polymorphic changes. All these parameters are

translated into bulk-level changes such as flow properties, compressibility, moisture sensitivity,

and machineability. Solid substances are characterized by three levels of solid-state: the

molecular, particle, and bulk level. These levels are closely linked to one another, with the

changes in one level reflecting in another level. The molecular level comprises the arrangement

of individual molecules in the crystal lattice and includes phenomena such as polymorphism,

pseudo-polymorphism, and the amorphous state. Particle level comprises individual particle

properties such as shape, size, surface area, and porosity. The bulk level is composed of an

ensemble of particles and properties such as flowability, compressibility, and dilution potential,

which are critical factors in the performance of excipients. A change at one level affects the other

levels. This interdependency among the levels provides the scientific framework for the

development of new grades/modification of existing excipients.



The fundamental solid-state properties of the particles such as morphology, particle size, shape,

surface area, porosity, and density influence excipient functionalities such as flowability,

compactability, dilution potential, disintegration potential, and lubricating potential. Hence, the

creation of a new excipient must begin with a particle design that is suited to deliver the desired

functionalities. Varying the crystal lattice arrangement by playing with parameters such as the

conditions of crystallization and drying can create particles with different parameters. It is also

possible to engineer particles without affecting the at molecular level. However, particle

engineering of a single excipient can provide only a limited quantum of functionality

improvement. A much broader platform for the manipulation of excipient functionality is

provided by co-processing or particle engineering two or more existing excipients. In order to

characterize a new excipient, the investigation of powder technological properties, including

flowability, crystallinity, and water content, is necessary as is the study of the tableting

properties.

Co processing: combinatorial engineering

Co-processing is the novel phenomenon of developing a new single-bodied excipient, interacting

two or more excipients at sub-particle level, the objective of which is to provide a synergy of

functionality improvement as well as masking the undesirable properties of individual excipients.

Co-processing was initially used by the food industry to improve stability, wettability, and

solubility and to enhance the gelling properties of food ingredients such as co-processed

glucomannan and galactomanan. Co-processed excipients are prepared by incorporating one

excipient into the particle structure of another excipient using processes such as co-drying or co-

precipitation. During this a common dispersion of the under processing excipients is made. Then

it is dried and converted into particulate of desirable size range by drying. Thus, they are simple

physical mixtures of two or more existing excipients mixed at the particle level, where one

particle interacts at the sub-particle level to form a single-bodied excipient. The combination of

excipients chosen should complement each other to mask the undesirable properties of individual

excipients and, at the same time, retain or improve the desired properties of excipients. For

example, if a substance used as a filler–binder has a low disintegration property, it can be co-

processed with another excipient that has good wetting properties and high porosity because

these attributes will increase the water intake, which will aid and increase the disintegration of

the tablets.

The actual process of developing a processed excipient involves the following steps:



Identifying excipient(s) to be processed by carefully studying the material characteristics

and functional requirements.

Selecting the proportions of various excipients if more than on excipient is selected for

the study

Assessing the particle size require for processing

Selecting a suitable process for drying and particle size reduction

Process optimization

Future perspective

The particular phenomenon of co-processed excipient is a field having vast scope for

development of excipient with desirable property for direct compression as well as for specific

method and formulation. The limitation of the existing excipients for new rapidly developing

API’s can be overcome. The process also opens opportunity for development and use of single

multifunctional excipient rather than multiple excipients in formulation. Now a day’s many

excipients are also being co-processed directly with API’s to develop a composition ready for

direct compression, e.g. co-spray drying of acetaminophen, mannitol, erythritol, maltodextrin

and a super disintegrant in spray dryer yields powders with improved tablet disintegration in

combination with acceptable physicochemical powder properties, tablet hardness and friability,

while Kollidon CL minimised tablet disintegration time. Also some of the excipients can be co-

processed to have a better physio-chemical property, e.g. granules of Carbopol and MCC

prepared from dried sodium hydroxide solution is pressed into tablet and is used for treatment of

gastro-esophageal reflux. Newer excipients are being developed to aid in targeted drug delivery

e.g peptide Dalargin to brain using Polyisobutyl cyano acrylate whose surface is being modified

with Tween 80.The availability of a large number of excipients for co-processing ensures

numerous possibilities to produce tailor-made “designer excipients” to address specific

functionality requirements.

Regulatory concern

As excipients are incorporated in the final formulations that also remain in the final product

they should have safety concern. To support marketing authorisation (MA) applications,

increased information is required on active ingredients. Genuinely new excipients, those not



previously registered with the regulatory authority, are to undergo a full safety evaluation,

because of the requirement in Directive 75:318: EEC. Compatibility of excipients with other

ingredients may have to be demonstrated in the development pharmaceutics and analytical

validation (European Commission, 1998b.) sections of the MA application dossier. An excipient

can be the subject of a ‘PhEur Certificate of Suitability’ (Council of Europe Public Health

Committee (Partial Agreement), Resolution AP-CSP (98) 2, Certification of suitability to the

monographs of the European Pharmacopoeia (revised version, March 1998).) which can partly

and sometimes fully satisfy the data requirements, within a MA application dossier, for that

ingredient (European Commission, 1998c). With the absence of a chemical change during

processing, co-processed excipients can be considered generally regarded as safe (GRAS) if the

parent excipients are also GRAS-certified by the regulatory agencies.

Thus in conclusion we can say that, excipient mixtures or processed excipients have yet to find

their way into official monographs, which is one of the major obstacles to their success in the

marketplace. The success of any pharmaceutical excipient depends on quality, safety, and

functionality. Although the first two parameters have remained constant, significant

improvements in functionality open the door for the increased use of processed excipients. The

advantages of these excipients are numerous, but further scientific exploration is required to

understand the mechanisms underlying their performance. With development a number of new

chemical entities rising day by day, there is a huge scope for further development of and use of

these excipients in future. Exploring material property of natural polymers and co-processing

them with the existing ones will create a large inventory of new developed excipients. Rather

than developing an entirely new excipient which would have to undergo a full safety evaluation,

and would be enormously expensive, it is better to develop physico-mechanical property of an

established product.

Starch

Starch is one of the most commonly used excipients. Depending on the concentration and

method of addition, its use varies such as disintegrant, thickener, binder, and diluent. Starch

carries a combination of amylose and branched amylopectin. Both polymers are arranged in a



semicrystalline pattern. The different configuration of amylose and amylopectin results in

different behavior in cold aqueous conditions.

Amylose exhibits higher tendencies towards crystallization resulting in insoluble adducts, while

amylopectin exhibits slow jellification, forming highly translucent and opaque systems over the

period. Starch is a GRAS-, IIG-, and U.S. Pharmacopeial Convention (USP)-listed material and

officially acceptable by all major regulatory agencies for its use in various oral drug delivery

systems (Rowe et al., 2009).

Prior art reveals various methods of preparation of porous starch (PS), such as enzymatic

hydrolysis of noncrystalline regions of granular starch at subgelatinization temperature

(Uthumporn et al., 2010), hot melt co-extrusion of corn starch and starch acetate (Guan et al.,

2004), microwave treatment of starch (Torres et al., 2007), and supercritical fluid extrusion

where supercritical carbon dioxide was used as a blowing agent (Manoi et al., 2010).

Intermolecular bonds of starch can be broken in the presence of heat and water. These broken

sites are available to form hydrogen bonds with water. Thus, this water penetration results into

decreased crystalline regions within starch and increased randomness which is exhibited by pore

formation. Since direct drying of hydrogel may result into collapse of porous structures, water

replacement from hydrogel with ethanol to form alcogel is important to maintain the porous

structure. Therefore, we have implied a solvent exchange method for the formulation of porous

starch.

Chapter III: Porous Starch: a Novel Carrier Rational and Objective


Rational

Starch is the most widely used filler-binder for its availability and lower cost. In tablet

formulation, freshly prepared starch paste is used at a concentration of 5-25% w/w in tablet

granulation as binder. They have also good disintegration property. However, unmodified starch

does not compress well and tends to increase tablet friability and capping. But the more

hygroscopic character and lower dilution potential leads to co-process physico-mechanically

developed excipients of starch. In view of the present scenario we thought to modify the

morphology of maize starch so as to overcome the associated disadvantages. The starch can be

given a porous structure which can positively be utilized for better flow and compressibility of

starch. The developed starch would also be evaluated as a carrier and solubility enhancer. Thus

the developed starch would be explored as a multipurpose but yet single excipient to be used in

fabrication of novel drug delivery systems.

Objective

To modify the physical properties of neat starch

To characterize and compare neat and developed starch

To use the developed porous starch into formulation

To evaluate the developed formulation

Chapter III: Porous Starch: a Novel Carrier Experimental


A. STANDARDIZATION OF NEAT STARCH

Physical characterization

Description

The starch sample was observed for color and appearance.

Melting point

Starch was filled in capillary tube, sealed at one end. The temperature at which the solid starts to

pass in liquid phase was recorded.

Particle size distribution

A series of meshes in descending order (of mesh opening size) was stacked one below another

and 100 g of starch was placed at the top. The sieves were then vibrated for 15 min in order to

get sifted through their corresponding sizes. The fractional quantity of starch on each sieve was

determined and noted down.

Loss on drying

All starches are hygroscopic and absorb atmospheric moisture to reach the equilibrium humidity

(Rowe, 2006). A predefined quantity of powder sample was placed uniformly on the plate of

Citizen, India (loss on drying) machine and heated to 105°C till a constant weight was achieved.

The machine values for % LOD were determined and expressed as moisture content.

Moisture uptake studies

The pre-weighed quantities of starch powders (Wi = 1.5g) were spread uniformly on petri plates

and left exposed to the environment for overnight. Further the weight gain of the samples was

recorded (Wf) and moisture uptake was expressed as:

Moisture uptake of the sample (%) = (increase in weight of the sample)*100/ (initial weight of

the sample)

Moisture uptake of the sample (%) = (Wf-Wi)*100/Wi ----------------------------(3.1)



Swelling determination

A predefined volume of starch powder (10 mL) in a cylinder was filled. To this cylinder distilled

water was added to make the total volume of 100 mL. The system was kept for 24 hours and then

the volume of starch was determined. This volume was expressed as percent swelling of powder.

Flow properties evaluation

The flow of neat and porous starch was characterized by angle of repose (θ). A funnel was fixed

5 cm above a base plate. Fifteen grams of powder was placed in a funnel and allowed to pass

through it and fall on the base plate so as to form a pile. The height (h) and diameter (d) of the

pile were measured, and the angle of repose was determined as follows:

Angle of repose θ = tan-1

(2h/d) ------------------------------------(3.2)

The compressibility index of powder was determined using equation number 3.3:

Compressibility index % Ci = (Vi - Vf)*100/Vi ------------------(3.3)

where Vi is the untapped apparent volume and Vf is the final tapped volume of the sample after

tapping the material until no further volume changes were observed.

Chemical Characterization

pH test

1% suspension of starch was prepared in distilled water and subjected for pH determination.

Fourier transform infrared spectroscopy

To confirm the presence of all functional groups and characterize the given starch chemically

FTIR scan was performed. Fourier transform infrared spectroscopy (FTIR) spectrometer from

PerkinElmer (USA) was used in an attenuated total reflectance manner to obtain FTIR spectra.

The samples were ground thoroughly with potassium bromide at 1:100 (sample/potassium

bromide) weight ratios in a mortar and pestle till a uniform mixture is observed. Scans were

performed in triplicate from 4,000 to 400 cm–1

at a resolution of 4 cm–1

.

Residue on ignition



A ceramic crucible was heated to redness for 10 minutes, allowed to cool in a desiccator and

weighed. About 1 g of the substance was accurately weighed into the crucible, ignited, gently at

first until the substance was thoroughly charred. This was cooled and residue moistened with 1

mL of sulphuric acid. This was heated gently until white fumes were no longer evolved and

ignited at 800 OC until all black particles disappeared. The crucible was allowed to cool and

weighed. This operation was repeated until two successive weighing did not differ by more than

0.5 mg.

B. GENERAL PROCEDURE FOR THE FORMULATION OF POROUS STARCH

Fig. 3.1. Brief schematic of formulation development

A certain quantity of starch powder was dispersed in distilled water at room temperature. The

dispersion system was stirred continuously to minimize the settling of starch particles. In another

Boiling waterBoiling

water

Star

ch s

usp

en

sio

n

Translucent Gel Solvent exchange (alcogel formation)

Drying

Sizing

Porous Starch

Dru

g lo

adin

g

Form

ula

tio

nIn vivo study

In vitro dissolution Characterizations70



beaker distilled water was heated to its boiling point. The starch dispersion prepared beforehand

was added to the boiling water under rapid stirring. The system was then slowly brought down to

room temperature while maintaining the stirring. The gel so formed was equilibrated at room

temperature for 2 hours and then stored at 8°C for 24 hours. After achieving equilibration the gel

was cut in cube shaped pieces of size ca. 1 cm3. These cubes were additionally frozen at 0°C so

as the water present within the gel should attain a crystalline structure. These frozen cubes

(hydrogel) were then immersed in alcohol so as to replace the water present inside gel with

alcohol and form an alcogel.

The alcogel was slowly dried under reduced pressure using R/210 Buchi (Germany) rotary

evaporator at low temperature of 30°C to avoid the structure collapse within the alcogel. The

dried materials was then recovered, dried for some more time at 60°C and then subjected for

particle size reduction and sifting. This material was termed as PS followed by a number,

depending on the change in formulation variable.

C. OPTIMIZATION OF PROCESS OF FORMULATION OF POROUS STARCH

Effect of starch concentration

The quantity of starch per unit quantity of water (% w/w) is an important factor to formulate a

good starch gel. The batches were taken in following manner. A variable quantity of starch (as

shown in table) was dispersed in 40 mL cold water and then the dispersion was added to 60 mL

hot boiling water under rapid stirring.

Table 3.1. Batches with their corresponding starch concentration

Batch number Quantity of starch per unit quantity of water (%w/w)

PS1 4

PS2 6

PS3 8

PS4 10

PS5 12

PS6 14



These batches were checked for their pour-ability. As soon as the gel is formed and brought

down to room temperature the gel was transferred to another vessel by pouring. The pouring

behavior was observed.

Effect of alcohol concentration

Equilibrated gel was weighed and dipped into the same quantity of solvent (alcohol-water

mixture / pure alcohol) for solvent exchange. The solvent exchange program was done on 4

different levels of alcohol concentration. The alcohol-water mixture was prepared in various

concentrations and expressed as %w/w concentration of alcohol.

Table 3.2. Batches with the respective alcohol concentration for solvent replacement

Batch number Alcohol concentration (% w/w)

PS7 25

PS8 50

PS9 75

PS10 100

To check whether the water from hydrogel has been replaced by alcohol the cube was weighed

(CI) was dried at 80°C for 2 hours and then the weight was noted (CII). The same cube is

subjected to drying above 105°C for 5 hours and again weighed (CIII). The extent to which we

have replaced water from hydrogel with alcohol can be expressed by solvent replacement index

as follows:

CI = collective weight of alcohol, water and solid starch in a cube

CII = weight of solid starch with water in a cube

CIII = weight of solid starch in a cube

Therefore, weight of alcohol = CI-CII

And weight of water = CII-CIII



Solvent (alcohol) replacement index = weight of alcohol*100/(weight of alcohol + weight of

water)

Solvent (alcohol) replacement index = (CI-CII) * 100/ [(CI-CII) + (CII-CIII) ]

Solvent (alcohol) replacement index = (CI-CII) *100/ (CI- CIII) ------------------------------(3.4)

From the previous batches we found that it was necessary to increase the quantity of alcohol for

solvent replacement process as given in table 3.3.

Table 3.3. Batches with the respective alcohol concentration for solvent replacement

Batch number Number of times the absolute alcohol quantity used in comparison to that

of hydrogel, for solvent replacement

PS11 1

PS12 2

PS13 3

Effect of drug loading

A certain quantity of CBZ was dissolved in acetone followed by the addition of defined quantity

of PS particles (as shown in table 3.4) under stirring at 27±2°C. The stirring was continued till

acetone evaporates completely leaving behind free-flowing CBZ loaded PS particles (CBZ-PS).

The developed particulate system was subjected to dissolution study as discussed previously.

Table 3.4. Batch composition of drug loading on porous starch in different ratio

Batch number Carbamazepine quantity (g) Porous starch quantity (g)

CBZ:PS 1:0.5 2 1

CBZ:PS 1:1 1 1

CBZ:PS 1:5 1 5

CBZ:PS 1:10 1 10

CBZ:NS 1:1 1 1



Dissolution Kinetic Studies

The dissolution studies were performed in 900 mL of 1% SLS solution using USP type II

apparatus operated at 75 rpm and at 37°C. Sink condition was maintained throughout the study.

Each dissolution study was carried out in double triplicate. The aliquots taken at various time

intervals were diluted suitably to quantify the drug release spectrophotometrically at 287 nm.

The analytical method for CBZ has linearity within the range of 0–20 μg/mL and expressed by

the Eq. 3.5 as follows:

A = 0.0502C + 0.0042 ------------------------(3.5)

Where A is the absorbance of the test solution measured at λmax of 287 nm, and C is CBZ

concentration in micrograms per milliliter in the test solution.

Encapsulation efficiency studies

A concentrated drug solution was prepared (500 mg/mL). To the 10 ml of this solution 100 mg

of porous starch particles were added and the test tube was capped tightly. The system was

stirred at 10 rpm for 24 hours in a bath shaker at room temperature. The solid particles were

filtered collected and dried. These particles were then further subjected to the drug content

analysis by UV spectrophotometric method, developed previously.

Formulation of CBZ-PS tablets

CBZ-PS tablets having composition as shown in table 3.5 were formulated. The tablets were

made using a single punch tablet compression machine (Cadmach Machinery, India) with 8-mm

standard concave punches. The crushing strength of tablets was maintained at 7–9 kg/cm2.

Table 3.5. Tablet composition of CBZ-PS

Ingredients Quantity (mg/tab)

CBZ-PS (1:1) 200

Microcrystalline cellulose (MCC 102) 78

Polyvinyl pyrrolidone (Kollidone 90) 15

Sodium starch glycolate (Glycolys) 15

Colloidal silicon dioxide (Aerosil 200) 3



D. EVALUATION OF POROUS STARCH AND DEVELOPED FORMULATION

Particle size distribution, moisture uptake, % swelling, angle of repose, Ci, and pH were done as

described previously.

Specific Surface Area and Pore Size Distribution

The surface area of developed porous starch was determined using nitrogen sorption isotherms

through Brumauer– Emmett–Teller (BET) protocol. Nitrogen sorption studies were done using

ASAP2020 (Micromeritics, USA). Before initiation of the study, the powder sample was stored

in sample bulb and then subjected to 40°C under vacuum of 0.1 mPa overnight to facilitate

removal of moisture from the sample. The nitrogen sorption data were generated through a

relative pressure (p/p0) range of 0.0 to 1.0. The pore size distribution and pore volume were

calculated following Barrett–Joiner– Halenda protocol.

Thermal Studies

Differential scanning calorimeter (DSC) (Pyris 6 DSC, PerkinElmer, USA) with a thermal

analyzer, equipped with the Pyris software, was employed to obtain thermal data. The instrument

was calibrated prior to test the samples, using indium. Five milligrams of sample was placed in a

DSC aluminum sample pan and then crimped. Heat flow rate of 10°C/min was used to heat the

samples from 40°C to 220°C. Nitrogen was used as a purge gas. An empty crimped pan was used

as a reference pan.

Scanning Electron Microscopic Studies

Morphology of the particulate samples was evaluated using a scanning electron microscope

(SEM; 97 JSM- 6380LA, Jeol Ltd., Japan). Double-sided adhesive carbon tape was used to fix

the sample powders to an aluminum stub and it was made conductive for use in Jeol Sputter for 5

min at 10 mA by coating with gold and palladium layers in vacuum. The samples were then

loaded into the SEM to obtain scanning electron micrographs above ×100 resolution.

Fourier Transform Infrared Spectroscopy

Fourier transform infrared spectroscopy (FTIR) spectrometer from PerkinElmer (USA) was used

in an attenuated total reflectance manner to obtain FTIR spectra. The samples were ground



thoroughly with potassium bromide at 1:100 (sample/potassium bromide) weight ratio in a

mortar and pestle till a uniform mixture is observed. Scans were performed in triplicate from

4,000 to 400 cm–1

at a resolution of 4 cm–1

.

Powder X-ray Diffraction Studies

The X-ray diffraction patterns of particulate samples were recorded in a Rigaku powder X-ray

diffraction system (Miniflex, Japan) with Cu Kα as a source for radiation. The samples were run

over the most in formative range from 5° to 50° of 2θ values. The step scan mode was performed

with a step size of 0.02° at a rate of 2°/min.

Determination of Anticonvulsant Activity

The anticonvulsant activity of CBZ, CBZ-PS, and Tegretol was determined using the maximal

electroshock method. The use of animals for the study was approved by the animal ethics

committee of the Institute of Chemical Technology, Mumbai. The study was conducted in male

albino mice having a weight of 25–30 g. Each group was composed of six animals which were

fasted overnight prior to the study. CBZ and its formulations were administered orally in a dose

of 35 mg equivalent CBZ/kg body weight (Tayel et. al. 2008) in the following manner:

Table 3.6. Details of the dose received by each group

Group number Description

1 Half milliliter vehicle (0.25% sodium carboxy methyl cellulose in distilled

water) as control

2 Tegretol tablets powdered and then suspended in 0.5 mL vehicle, such that

these volumes contained the required dose

3 Neat CBZ in a required dose suspended in

0.5 mL vehicle

4 Received an amount of the powdered CBZ-PS

containing the animal dose suspended in 0.2 mL vehicle

Drug or formulation was administered to the animal, and after 1 h, an electrical stimulus (50 mA)

was applied for 0.2 s. An electrical simulator was used to deliver maximal electroshock seizure



(MES) stimuli. The electrodes were placed at the ear of the animal. The animals were held firm

by hand and freed at the time of stimulation so as to observe for the seizure. The drug could

prevent the MES spread if the animal fails to show hind limb tonic extensor. The results were

expressed as percent animals protected.

E. STABILITY STUDIES

To carry out these studies, the formulation was subjected to 25°C/60% relative humidity

(R.H), 30°C/65% R.H and 40°C/75% R.H as per the stability protocol (Table 3.7). Samples

were charged in stability chambers (Thermolab, India) with humidity and temperature control.

They were drawn at specified intervals for analysis over a period of 6 months. Drug content of

the tablets was analyzed using previously developed and validated stability indicating HPLC

method.

Table 3.7. Stability Protocol for CBZ-PS tablets

PRODUCT NAME: CARBAMAZEPINE TABLETS 100mg

BATCH NO. CBZ: PS 1:1

APPEARANCE white tablets

TOTAL NO SAMPLE (INCLUDING INITIAL) 400 tablets

QUANTITY FOR PHYSICAL/ CHEMICAL ANALYSIS 90 tablets

DATE OF STABILITY STARTED 03/2012

REGION FOR TESTING - 6 months (stability testing as per ICH guidelines)

Chapter III: Porous Starch: a Novel Carrier Results and Discussion


A. STANDARDIZATION OF NEAT STARCH

Physical characterization

Description

The starch was white odorless powder.

Melting point

Starch was found to be stable up to 250 °C and after that it showed degradation, with conversion

of white particles into blackish particles.

Particle size distribution

The size distribution analysis showed that the neat starch had a very fine size and major fraction

(70%) population has a particle size of less than 125 µ (table 3.8). Very low particle size often

results in higher surface area and more surface for interaction, which may be responsible for

good interlocking and cohesiveness of the powder and thereby causing poor flow.

Table 3.8. Particle size distribution of neat starch

Sieve number (ASTM) % Weight retained of neat Starch

≥20 3.75

40 0.25

60 0.20

80 0.50

100 1.75

120 21.26

≤140 72.28

Loss on drying

All starches are hygroscopic and absorb atmospheric moisture to reach the equilibrium humidity

(Rowe et al., 2006). The approximate equilibrium moisture is characteristic for each starch. The

loss on drying for the neat starch was found to be 15%.

Moisture uptake



The neat starch found to take around 14.34% moisture when exposed to controlled humid

environment.

Swelling determination

When the starch was suspended in water it did not show any considerable swelling behavior.

Upon slow increase in temperature starch showed swelling of 10% at 65ºC. The reported values

for swelling temperature for various starches are as follows:

Table 3.9. Type of starch and their swelling temperature (Rowe et al., 2006)

Starch type (source) Swelling temperature (ºC)

Corn 65

Potato 64

Wheat 55

Flow properties evaluation

The flow of sample (neat and porous starch) was characterized by angle of repose (θ).

Angle of repose = 38.69º

Compressibility index = 33.07%

Both of these values were towards higher side. It is always desirable to have these values as low

as possible in order to have good flow and compressibility.

Chemical Characterization

pH test

In order to determine whether the starch has acidic or alkaline nature in water, pH determination

test was performed. The pH of the 1% suspension was found to be 6.5 at 25ºC.

Fourier transform infrared spectroscopy



The FTIR spectrum of the neat starch is shown in fig 3.9. All the concerned functional groups

were found to be present in the sample. The result is discussed further under the FTIR

characterizations of porous starch.

Residue on ignition

This test utilizes a procedure to measure the amount of residual substance not volatilized from a

sample when the sample is ignited in the presence of sulphuric acid. This test usually gives a

measure about the content of inorganic impurities in an organic substance. Residue on ignition of

the neat starch was found to be 0.9%.

B. OPTIMIZATION OF PROCESS OF FORMULATION OF POROUS STARCH

Effect of starch concentration

In order to formulate a consistent gel with decent process-ability, we have varied a concentration

of starch from 4 % w/w to as high as 14% w/w. At lower concentration of starch the gel was

found to be less viscous whereas highly viscous paste was found beyond 10%w/w concentration

of starch. Therefore, depending upon the ease of incorporation, and ease of pour-ability (as

shown in table 3.10), we shortlisted 8% w/w as our final starch concentration.

Table 3.10. Effect of starch concentration on pour-ability

Batch number Pour-ability

PS1 Yes, easy to pour

PS2 Yes

PS3 Yes

PS4 Yes, slightly difficult to pour

PS5 Yes, difficult to pour

PS6 No

The principle we utilized here is breaking down the intermolecular bonds of starch in presence of

heat and water and these broken sites are available to form hydrogen bonds with water. Thus, in

case of highly viscous gels (which were difficult to pour) there may be chances that some of the



intermolecular bonds remained unbroken. This subsequently would result into lesser pore

volumes and surface area.

Effect of alcohol concentration

Increasing alcohol concentration from 25 to 100% showed a gradual increase in alcohol

replacement index as expected. Higher solvent replacement index was observed when absolute

pure alcohol was used for solvent exchange. The higher concentration gradient between the

aquagel and pure alcohol might have served as a driving potential for solvent replacement.

Fig. 3.2. Effect of alcohol concentration on solvent replacement index

When almost a 3 time’s alcohol of the initial weight of hydrogel was used, a sufficiently good

replacement was observed (around 98%). Therefore, we have proceeded with the alcogel which

has a good solvent replacement index, since this will be helpful in maintaining an undisturbed

porous structure.

0

10

20

30

40

50

60

PS7 PS8 PS9 PS10

Solv

en

t R

ep

lacem

en

t In

dex (

%)

Batch Number



Fig. 3.3. Effect of alcohol concentration on solvent replacement index

Effect of drug loading

Fig. 3.4. Dissolution profile of carbamazepine at different levels of loading

Rapid drug release profile was observed in case of CBZ-PS and Tegretal as compared to neat

CBZ (Fig. 3.4). The significantly improved dissolution profile for CBZ-PS might be due to (a)

high surface area of drug, (b) geometric confinement of CBZ within the pores of porous starch

thereby reducing the CBZ particle size, and (c) decreased crystallinity as evident from the

powder X-ray diffraction (PXRD) pattern and improved wettability.

0

20

40

60

80

100

120

PS11 PS12 PS13

Solv

en

t R

ep

lacem

en

t In

dex(%

)

Batch Number

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Dru

g R

ele

ase

d (

%)

Time (Min)

CBZ:PS 0.5:1

CBZ:PS 1:1

CBZ:PS 1:5

CBZ:PS 1:10

CBZ:NS 1:1



Further, the tablets of CBZ-PS (1:1) and neat CBZ were formulated. These tablets were

subjected to dissolution studies.

Fig. 3.5. Carbamazepine release profile from different tablet systems

The obtained dissolution data were tried to fit in Korsmeyer– Peppas (Eq. 3.6) (Ahuja et al.,

2007) model to identify the release mechanism of CBZ from formulation.

Mt/M∞ = ktn -------------------------------------------(3.6)

where Mt/M∞ is fraction of drug released at time t, k is release constant, and n is release

exponent and an indicative of release mechanism. To declare a system exhibiting Fickian

diffusional characteristics, the corresponding value of n should be lower than (Korsmeyer et al.,

1983) 0.45 for CBZ-PS indicating the system is following Fick’s law of diffusion. Tegretal

showed marginally high value of n signifying for slightly non-Fickian release behavior (Table

3.11). Neat CBZ had a significantly high n value illustrating mixed non-Fickian release

mechanism.

Table 3.11. Formulation Characterization Using the Korsmeyer– Peppas Equation

System k n

Neat CBZ tablet 0.002 0.702

CBZ-PS tablet (1:1) 0.865 0.042

Tegretal 0.157 0.475

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Dru

g r

ele

ase

d (

%)

Time (Min)

Neat CBZ

CBZ-PS Tablet

Tegrital Tablet



Encapsulation efficiency studies

The percent encapsulation efficiency was found to be 39.85%. Therefore if the drug and porous

starch were taken in a ratio of 1:1, it means that in a blend of 200 mg (which is equivalent to 100

mg of carbamazepine) 80 mg of carbamazepine would remain inside the channels of porous

starch whereas 20 mg would be at the channel/pore or surface of the porous starch. Similarly, we

can conclude that 40% encapsulation is sufficient to impart a significantly higher rate of

dissolution.

C. EVALUATION OF POROUS STARCH AND DEVELOPED FORMULATION

The general parameters were evaluated for the developed porous starch material for the

comparison purpose. The results along with the comments is shown in table 3.12.

Table 3.12. Evaluation parameters of porous starch

Property Result Remark

Particle size

distribution

Particle pass through

ASTM #40 and

retained on ASTM #60

The majority of fraction (80%) of the particle

population is #40 pass and #60 retained. Increase in

particle size was observed as compared to neat starch.

Moisture

uptake

17.37% The developed porous starch has a higher moister

upake as compared to neat starch (14.3%) and Starch

1500(16.43%)

Swelling index 40% A higher swelling behavior was observed as

compared to neat starch and Starch 1500 (30%)

Angle of

repose*

18.95% The angle of repose decreased significantly indicating

a good flow of porous starch.

Ci 17.93% This indicates an improvement in flow of PS and can

be used in directly compressible formulations.

pH 6.5 The pH was found to be same as of neat starch (6.5).

* Angle of repose and compressibility index is often used as simple, fast, and popular means to

predict the flow properties of powders. The smaller values of the angle of repose (≤30°) indicate

excellent flow property, whereas low Ci (≤20) signifies fair flow and little cohesiveness (USP

29, 2006).



Specific Surface Area and Pore Size Distribution

The nitrogen sorption curve (Fig. 3.6a) showed type IV isotherm displaying a monolayer

adsorption followed by multilayer adsorption of nitrogen on PS. Nitrogen condensation step

resulted in two hysteresis loops. The first loop ran from p/p0 value of 0.7 to 0.9 and responsible

for nitrogen condensation in mesopores (Wu et al., 2011). The second hysteresis loop (p/p0 of

0.9 to 0.99) was relatively hefty, signifying nitrogen condensation within the macropores.

Specific surface area determined by the BET method was found to be 109.73 m2/g. Major

populations of the pores were found to be around 200 nm (Fig. 3.6b) and total pore volume was

calculated as 0.32 mL/g.

(a)

Fig.3.6. a: Nitrogen adsorption isotherm for porous starch and b: Pore size distribution of porous

starch

0

50

100

150

200

250

300

0 0.2 0.4 0.6 0.8 1

Volu

me a

dso

rb

ed

(cc/g

ST

P)

Relative Pressure (p/p0)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0 50 100 150 200 250 300 350 400

Pore V

olu

me (

cc/g

)

Pore diameter (nm)



Thermal Studies

Figure 3.7. DSC thermo gram of a: CBZ, b: CBZ-PS, c: physical mixture of CBZ and PS, d:

Tegrital, e: neat starch and f: PS.

Sharp endothermic peak for carbamazepine was seen from different thermograms. Decreased

area under curve corresponding to reduced enthalpy for carbamazepine in case of CBZ-PS

signified that there was little reduction in crystallinity of carbmazepine. A complexation effect of

carbamazepine in CBZ-PS was mainly responsible for observed modified calorimetric pattern of

CBZ-MS. It was evident from the thermal behavior of carbamazepine (Fig. 3.7), which took

place in three phases. Initially, carbamazepine (which was in form III) melted at around 174°C

then recrystallized to “form I” as shown by an exothermic peak and then again a sharp

endothermic peak at 193°C for melting of carbamazepine form I, concluding that carbamazepine

was in polymorphic monoclinic form III (Grzesiak et al., 2003). The physical mixture of

carbamazepine and PS resulted in wider and weaker melting peak indicating a dilution effect and

little interaction through hydrogen bonding. Both starches, neat as well as porous, showed very

subtle thermal behavior and were found to be remained almost unaffected. Tegretal performed in

a different way indicating the presence of carbamazepine in a different form other than “form

III.”



Scanning Electron Microscopic Studies

Neat CBZ (Fig. 3.8c) displayed glistening appearance with crystalline coarser particles. The

surface of neat starch (Fig. 3.8a) showed trivial roughness, indicating less likelihood for

interaction with other chemical moieties. PS (Fig. 3.8b) showed spongy morphology which could

be positively tendered for interaction with the drug. Figure 3.8d exhibited a nicely intermingled

carbamazepine within porous starch. Majority of the pore volume and area found to engage with

carbamazepine resulting into suppressed recrystallization of carbamazepine.

Fig. 3.8. SEM images of a: neat starch. b: Porous starch, c: neat carbamazepine and d:

carbamazepine loaded porous starch

Fourier Transform Infrared Spectroscopy

FTIR of the neat starch and PS were found to be comparable as shown in Fig. 3.9. In case of PS,

the intensity of peaks decreased and smoothening of the peaks was observed, when compared

with the neat starch. This may be due to the fact that pore formation in PS may have resulted in

decreased starch granular density (Zhang et al., 2012). Important peaks (Vasko et al., 1972)

characterizing starch are 764 cm−1 (C–C stretch), 1,067 cm−1 (C–H bending), 1,344 cm−1 (C–

O–H bending and –CH2 twisting), and 3,165 cm−1 (−CH2 deformation) (Cael et al., 1973).

Carbamazepine is characterized by the presence of 3,465 cm−1 (−NH2 vibration), 1,677 cm−1 (–

CO–R vibration), and 1,605 and 1,593 cm−1 (–C=C– vibration C=O vibration and deformation

of –NH) (Ambrogi et al., 2008). The presence of peak at 3,161 cm−1 signified that

carbamazepine is in its polymorphic form III (Grzesiak et al., 2003). Hydrogen bonding and

steric hindrance are often used as a tool to describe the interaction of drug and carrier (Dinunzio

et al., 2008) and carbonyl group remains a powerful hydrogen bond acceptor (Chan et al., 2011)

which can form a hydrogen bond with the terminal hydroxyl group of glucose units present in



porous starch as evident from the decreased peak intensity of carbonyl group and C–H peak

broadening in CBZ-PS system.

Fig 3.9 FTIR of a: neat starch, b: PS, c: CBZ-PS, d: neat CBZ and e: physical mixture of PS and

CBZ.

Powder X-ray Diffraction Studies

X-ray diffraction (XRD) of CBZ exhibits presence of peaks at 2θ values at with very narrow

crystal size as indicated by low peak width. Important 2θ values of CBZ were 13.14, 13.71,

15.03, 15.36, 15.93, 17.17, 18.69, 19.56, 20.56, 22.07, 23.45, 25.00, 26.40, 27.47, 29.44, and

30.08 which revealed the presence of polymorphic form III of CBZ which is in good agreement

with literature values (Grzesiak et al., 2003). The background bump in the XRD pattern

corresponding to amorphousness of the compound was found to be gradually increasing from

neat carbamazepine, physical mixture of carbamazepine, and PS to CBZ-PS system. The

amorphous systems contain more free energy which often serves as a driving potential for



solubility; therefore, these systems are more soluble as compared to that of their crystalline

counterpart (Corrigan et al., 1984).

Fig. 3.10. XRPD of a: neat starch, b: PS, c: CBZ-PS, d: physical mixture of CBZ and PS and e:

CBZ.

Determination of Anticonvulsant Activity

The MES method used to determine anticonvulsant activity is simple, precise, rapid, and reliable

as compared to the other methods reported elsewhere such as the use of pharmacodynamics

markers (Clinckers et al., 2005), direct cortical stimulation (Hoogerkamp et al., 1994), and

electroencephalogram (Paschoa et al., 1994). The outcome for in vivo anticonvulsant activity by

MES method is shown in Table 3.13.

Table 3.13. Anticonvulsant activity amongst various groups

Group Number Number of animals exhibiting convulsion Protection (%)

1 6/6 Zero

2 0/6 100

3 4/6 33.33 4 0/6 100

The anticonvulsant activity for CBZ-PS was found to be excellent and comparable with that of

Tegretal. This might be due to improved solubility and dissolution rate of carbamazepine from

CBZ-PS making carbamazepine readily available for absorption. Literature is well entrenched



with the porous starch formulation strategies. However, these methods pose problems of multiple

freezing cycles (Qian et al., 2011), longer periods of equilibration (Wu et al., 2011), crosslinking

of starch (Qian et al., 2012), and equipment intensiveness (Manoi et al., 2010). On the contrary,

the present method is facile, less time consuming, cost effective, and industrially feasible.

D. SABILITY STUDIES

The carbamazepine content of the developed formulation remained unaffected over the period of

storage at different condition.

Table 3.14. Stability data of carbamazepine tablets

Storage condition Time (months) Assay (%) Friability (%) Disintegration (seconds) Hardness (kg/cm2)

25 oC/ 60% RH 0 100 0.121 45 7

25 oC/ 60% RH 1 100 0.153 60 5

25 oC/ 60% RH 2 101 0.161 50 9

25 oC/ 60% RH 3 99.5 0.171 54 8

25 oC/ 60% RH 6 100 0.121 48 7

30 oC/ 65% RH 1 100 0.198 68 9

30 oC/ 65% RH 2 99.5 0.372 79 8

30 oC/ 65% RH 3 99.3 0.349 65 5

30 oC/ 65% RH 6 102 0.148 62 7

40 oC/ 75% RH 1 99 0.210 73 9

40 oC/ 75% RH 2 103 0.385 69 8

40 oC/ 75% RH 3 99.9 0.343 38 6

40 oC/ 75% RH 6 101 0.321 63 7

Dissolution studies

The drug release profiles for the stability sample are shown in figure 3.11. The drug release was

found to be almost unaltered over the period.



(a)

(b)

(c)

Fig. 3.11. Dissolution pattern of carbamazepine from CBZ-PS 1:1 tablets at a: 25ºC/60% RH, b:

30 ºC /65% RH and c: 40 ºC /75 %RH

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Dru

g R

ele

ase

d (

%)

Time (Min)

CBZ-PS Tablets (Initial)

1 Month

2Months

3 Months

6 Months

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Dru

g R

ele

aa

sed

(%

)

Time (Min)


1 Month

2Months

3 Months

6 Months

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Dru

g R

ele

ase

d (

%)

Time (Min)


1 Month

2Months

3 Months

6 Months



Further scope for work

In this work the process of cooling was carried out in a domestic refrigerator, another study

could be planned for the effect of rate of cooling on pore size distribution. Literature reports that

the slower the rate of cooling applied more uniform and smaller crystals we get. Therefore, we

can devise a study where the effect of rate of cooling of 1 cm3 gel on the pore size distribution

can be studied within the resulting porous starch.

Chapter III: Porous Starch: a Novel Carrier Conclusion


Conclusion

A successful process has been developed to prepare PS from neat starch. In the present study,

successful use of PS is demonstrated for the solubility improvement of CBZ. The developed

CBZ-PS systems were characterized with respect to dissolution kinetics, SEM, XRD, IR, and

DSC. CBZ-PS systems showed an improved in vivo performance as compared to Tegretol and

neat CBZ. Thus, PS can be used as a solubility enhancer and carrier for various other drug

candidates.

Chapter III: Porous Starch: a Novel Carrier References


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