SOLID DISPERSION
Definition: The technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage.
Need of solid dispersion:
Increases Oral bioavailability of a drug
Increased dissolution rate.
Enhanced release of drugs from ointment.
Improved the solubility & stability.
The concept of solid dispersion was originally proposed by Sekiguchi & obi.
Increasing the dissolution, absorption & therapeutic efficacy of drugs in dosage forms.
Increasing solubility in water.
Improving the oral absorption and bioavailability of BCS Class II drugs.
Evaluation methods for drug excipients and container interactionSagar Savale
Excipients are one of the three components that in combination produce the medicine that the patient will take.
In therapeutic terms, the API is of primary importance because without it there is no treatment and no product.
In term of drug manufacturing all three of them are equally important so we cannot neglect anyone of them.
The interactions between excipients and the other two components (the API and the manufacturing process), and/or between two or more excipients, are fundamental to the transformation of an API into a medicinal product.
SOLID DISPERSION
Definition: The technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage.
Need of solid dispersion:
Increases Oral bioavailability of a drug
Increased dissolution rate.
Enhanced release of drugs from ointment.
Improved the solubility & stability.
The concept of solid dispersion was originally proposed by Sekiguchi & obi.
Increasing the dissolution, absorption & therapeutic efficacy of drugs in dosage forms.
Increasing solubility in water.
Improving the oral absorption and bioavailability of BCS Class II drugs.
Evaluation methods for drug excipients and container interactionSagar Savale
Excipients are one of the three components that in combination produce the medicine that the patient will take.
In therapeutic terms, the API is of primary importance because without it there is no treatment and no product.
In term of drug manufacturing all three of them are equally important so we cannot neglect anyone of them.
The interactions between excipients and the other two components (the API and the manufacturing process), and/or between two or more excipients, are fundamental to the transformation of an API into a medicinal product.
Technology Transfer in Pharma Industry, Technology Transfer in Pharmaceutical Industry, Pharmaceutical Technology Transfer, Pharma Tech Transfer, Naseeb basha, Pharmaceutical Tech Transfer, Naseeb basha Technology Transfer in Pharma Industry, Naseeb basha Pharmaceutical Technology Transfer
Superdisintegrants in Orally Administered Products of Pharmaceuticals A Reviewijtsrd
Superdisintegrants are developed to improve the palatability in orally administered products and to advancing the development of various formulations with increase performance and acceptability. Superdisintegrants are used to revise the potency of solid dosage form .This is accomplish by decreasing the disintegration time which in turn improvement the drug dissolution rate. Diverse categories of Superdisintegrants such as synthetic, semi synthetic, natural and cross processed blend etc. The present study comprises the various kinds of Superdisintegrants which are being used in formulations to provide the safer effective drug delivery with patient’s compliance. Snehal N. Dhoot | Sharda P. Shahane | Kiran. P. Gaikwad | Leena P. Joge | Jaya P. Ambhore "Superdisintegrants in Orally Administered Products of Pharmaceuticals: A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50282.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50282/superdisintegrants-in-orally-administered-products-of-pharmaceuticals-a-review/snehal-n-dhoot
Oral controlled drug delivery systems - Various Approaches SIVASWAROOP YARASI
these are the drug delivery systems which are given orally and the drug release is such that it releases at a controlled way at a predetermined rate for a particular period of time.
Bilayer tablet is suitable for sequential release of two drugs in combination and also for controlled release tablet in which one layer is for immediate release as initial dose and the second layer is for controlled release or maintenance dose. Bilayer tablet is an improved beneficial technology to overcome the shortcoming of the monolayer tablet. This technology avoids frequent administration of dosage form. Now a days such technology is used for co-administration of two drugs like anti-diabetic, anti-hypertensive, anti-inflammatory to the patients. Conventional solid oral dosage forms are a traditional approach, but bilayer tablet is a novel approach that requires new machinery for manufacturing. The technique is cost effective, safe and reproducible.
Formulation and evaluation of Muco adhesive Buccal Tablets of Ramprildoddaapurupa
The buccal mucosa lines the inner cheek and Buccal formulations are placed in the mouth between upper gingiva(gums) and cheek to treat local and systemic conditions.
Drugs which undergoes Extensive first pass metabolism and drug degradation in acidic media, GI tract can be administered through buccal route.
The oral cavity has been used as a site for local and systemic drug delivery.
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Superdisintegrants in Orally Administered Products of Pharmaceuticals A Reviewijtsrd
Superdisintegrants are developed to improve the palatability in orally administered products and to advancing the development of various formulations with increase performance and acceptability. Superdisintegrants are used to revise the potency of solid dosage form .This is accomplish by decreasing the disintegration time which in turn improvement the drug dissolution rate. Diverse categories of Superdisintegrants such as synthetic, semi synthetic, natural and cross processed blend etc. The present study comprises the various kinds of Superdisintegrants which are being used in formulations to provide the safer effective drug delivery with patient’s compliance. Snehal N. Dhoot | Sharda P. Shahane | Kiran. P. Gaikwad | Leena P. Joge | Jaya P. Ambhore "Superdisintegrants in Orally Administered Products of Pharmaceuticals: A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50282.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50282/superdisintegrants-in-orally-administered-products-of-pharmaceuticals-a-review/snehal-n-dhoot
Oral controlled drug delivery systems - Various Approaches SIVASWAROOP YARASI
these are the drug delivery systems which are given orally and the drug release is such that it releases at a controlled way at a predetermined rate for a particular period of time.
Bilayer tablet is suitable for sequential release of two drugs in combination and also for controlled release tablet in which one layer is for immediate release as initial dose and the second layer is for controlled release or maintenance dose. Bilayer tablet is an improved beneficial technology to overcome the shortcoming of the monolayer tablet. This technology avoids frequent administration of dosage form. Now a days such technology is used for co-administration of two drugs like anti-diabetic, anti-hypertensive, anti-inflammatory to the patients. Conventional solid oral dosage forms are a traditional approach, but bilayer tablet is a novel approach that requires new machinery for manufacturing. The technique is cost effective, safe and reproducible.
Formulation and evaluation of Muco adhesive Buccal Tablets of Ramprildoddaapurupa
The buccal mucosa lines the inner cheek and Buccal formulations are placed in the mouth between upper gingiva(gums) and cheek to treat local and systemic conditions.
Drugs which undergoes Extensive first pass metabolism and drug degradation in acidic media, GI tract can be administered through buccal route.
The oral cavity has been used as a site for local and systemic drug delivery.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Formulation and Evaluation of Amlodipine Fast Dissolving Tabletsijtsrd
Fast dissolving tablet is a new era for successful development of controlled release formulation along with various features to provide successful drug delivery. In the present study, an attempt was made to design and evaluate fast dissolving tablets of Amlodipine besylate, which is used commonly for the treatment of angina pectoris. The tablets were prepared by direct compression method followed by sublimation method using super disintegrants sodium starch glycolate, crosspovidone and croscarmellose sodium. The prepared powder blends were evaluated for preformulation parameters. The tablets were evaluated for thickness, hardness, weight variation, drug content uniformity, friability and in vitro drug release studies. In vitro drug release studies were performed by using USP type II apparatus paddle method at 50 rpm in 900 ml of 0.1N HCl as dissolution medium for 30 minutes at 37±0.5°C. The formulation F9 containing Croscarmellose sodium 7 showed better disintegration and dissolution up to 30 minutes. Hence, formulation F9 was considered as optimized formulation which showed the best drug release profile up to 30 minutes. The results of mathematical model fitting of data obtained indicated that, the best fit model in all the cases the release was found to be by diffusion and fickian release. The results of FTIR analysis showed that there was no physical and chemical interaction between drug and other excipients. The study indicates that the fast dissolving tablets of Amlodipine besylate can effectively reduce the adverse effects and frequency of administration of the drug. Aparna. P | Dr. Subash Chandran M. P | Remya S B "Formulation and Evaluation of Amlodipine Fast Dissolving Tablets" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-1 , December 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29563.pdfPaper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/29563/formulation-and-evaluation-of-amlodipine-fast-dissolving-tablets/aparna-p
Formulation and evaluation of fast dissolving tabletsSURYAKANTVERMA2
The concept of mouth dissolving drug delivery systems (MDDDS) or fast dissolving tablets emerged with an objective to improve patient’s compliance.
These dosage forms rapidly disintegrate and/or dissolve to release the drug as soon as they come in contact with saliva, thus obviating the need for water during administration, an attribute that makes them highly attractive for pediatric and geriatric patients.
Background: The main objective of present research work is to formulate the Carbamazepine Fast Dissoving tablets. Carbamazepine, an
antiepileptic, belongs to BCS Class-II and used to control some types of seizures in the treatment of epilepsy and Neuropathic Pain by
blocking use-dependent sodium channels. Methods: The Fast Dissoving tablets of Carbamazepine were prepared employing different
concentrations of Crospovidone and Croscarmellose sodium in different combinations as a Sperdisintegrants by Direct Compression technique
using 32
factorial design. The concentration of Crospovidone and Croscarmellose sodium was selected as independent variables, X1
and X2 respectively whereas, wetting time, Disintegration time, t
50% ,t90%were selected as dependent variables. Results and Discussion:
Totally nine formulations were designed and are evaluated for hardness, friability, thickness, Assay, Wetting time, Disintegration time, Invitro
drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitro
dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) &
regression coefficient (r) were calculated. Polynomial equations were developed for Wetting time, Disintegration time, t50%, t90%. Validity of
developed polynomial equations were verified by designing 2 check point formulations (C1
, C2
). According to SUPAC guidelines the
formulation (F5
) containing combination of 9.375% Crospovidone and 9.375% Croscarmellose, is the most similar formulation (similarity factor
f
2
=82.675, dissimilarity factor f1
= 2.049 & No significant difference, t= 0.041) to marketed product (TEGRETOL-100). Conclusion: The
selected formulation (F5
) follows First order, Higuchi’s kinetics, mechanism of drug release was found to be Non-Fickian Diffusion (n= 0.665).
KEYWORDS: Carbamazepine, 3
2Factorial Design, Crospovidone , croscarmellose Sodium, Wetting Time, Disintegration Time.
The oral route is the most favorable route for administration of drugs because of accurate dosage, low cost of therapy, self medication, non-invasive method, and ease of administration leading to a high level of patient compliance. Of the oral Dosage forms, solid dosage form is the preferred class of product as tablet represents a unit dosage form in which one dose of drug is placed accurately.
The main objective of the present research work is to formulate the Clopidogrel Fast Dissolving tablets. Clopidogrel, an antiplatelet drug, belongs to BCS Class-II and used to control Heart attack, Hypertension by inhibiting Platelet activation and aggregation .The Fast Dissolving tablets of Clopidogrel were prepared employing different concentrations of Crospovidone and Croscarmellose sodium in different combinations as a Superdisintegrant by Direct Compression technique using 32 factorial design. The concentration of Crospovidone and Croscarmellose sodium was selected as independent variables, X1 and X2 respectively whereas, wetting time, Disintegration time, t50%, t90% were selected as dependent variables. Totally nine formulations were designed and evaluated for hardness, friability, thickness, Assay, Wetting time, Disintegration time, and in-vitro drug release. From the Results it was concluded that all the formulation were found to be with in the Pharmacopoeial limits and the in-vitro dissolution profiles of all formulations were fitted into different Kinetic models, the statistical parameters like intercept (a), slope (b) and regression coefficient (r) were calculated. Polynomial equations were developed for Wetting time, Disintegration time, t50%, t90%. Validity of developed polynomial equations was verified by designing 2 check point formulations (C1, C2). According to SUPAC guidelines, the formulation (F5) containing combination of 15% Crospovidone and 15% Croscarmellose, is the most similar formulation (similarity factor f2=91.3936, dissimilarity factor f1= 1.203& No significant difference, t= -0.00062) to marketed product (PLAVIX-75). The selected formulation (F1) follows First order, Higuchi’s kinetics, mechanism of drug release found to be Fickian Diffusion (n= 0.226).
Formulation development and invitro evaluation of lamotrigine fast dissolving...SriramNagarajan19
The present study was to formulate and evaluate oral fast dissolving Oral tablet containing Lamotrigine. Present study reveals that all the nine formulated tablet showed satisfactory tablet parameters. It can be concluded that, Oral fast dissolving tablet -containing Lamotrigine can be prepared by direct compression method. 10% CCS (FV) tablet exhibited required disintegration time and dissolution time. The drug release was about 98.7 % in 15min. The accelerated stability studies of the optimized F5 formulation indicates that the formulated oral fast dissolving tablet were unaffected after 3 months storage under accelerated conditions as there were no signs of visually distinguishable changes in appearance, disintegration time and cumulative percentage of drug release. From the present investigation it can be concluded that oral fast dissolving tablet formulation can be a potential novel drug dosage form for pediatric, geriatric and also for general population.
ABSTRACT
The aim of the present research work was to enhance the solubility of
Carvedilol by solid dispersion method and to formulate a mouth
dissolving tablet. Drugs are more frequently taken by oral
administration. The solubility of Carvedilol enhanced with different
ratios of PVP by the solvent evaporation method .In-vitro release
profile of solid dispersion obtained in SGF without enzymes and Ph
6.8 phosphate buffer indicate that 100% drug release found within 20
min. These solid dispersion were directly compressed into tablets using
Crospovidone, sodium starch glycol ate, croscarmellose sodium and
polyacrylic potassium in different concentrations as a super
disintegrants. The prepared tablets containing the solid dispersion of
Carvedilol having sufficient strength of 2.5-4 kg/cm2. The
disintegrated in the oral cavity with in 21 sec. contain Crospovidone
(5%) as super disintegrant.
KEYWORDS: Carvedilol, PVP, Super Disintegrants, Mouth Dissolving Tablet.
Formulation Development and Evaluation of Mouth Dissolving Film of Ziprasidon...ijtsrd
The primary objective of this work was to develop a mouth dissolving film with Ziprasidone HCI, along with bioenhancer quercetin and basic ingredients like polymers, plasticizers, sweetener, saliva stimulating agent and flavor. The films were prepared by solvent casting I method. Quercetin enhances dissolution of drug which results in increase in CDR upto 99 . HPMC E5 cps, which was not able to impart thickness to the film, HPMC E15 shown good flexibility. The plasticizer propylene glycol which was not able to impart flexibility and folding endurance to the film. PEG 400 produced good folding endurance, tensile strength and percent elongation. The optimized formulation F3 was shown good mouth feel, folding endurance, instant drug release as well as good mechanical properties. The F3, shown less disintegration time of 31 seconds and 95 drug released within 3 minutes. Therefore it was concluded that rapid drug release was achieved for immediate onset of action using quercetin as natural bioenhancer which is beneficial and gives maximum drug release when compared to conventional dosage form. Jaydeep Jadhav "Formulation Development and Evaluation of Mouth Dissolving Film of Ziprasidone Using Natural Bioenhancer" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-5 , August 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50464.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50464/formulation-development-and-evaluation-of-mouth-dissolving-film-of-ziprasidone-using-natural-bioenhancer/jaydeep-jadhav
Personal Brand Statement:
As an Army veteran dedicated to lifelong learning, I bring a disciplined, strategic mindset to my pursuits. I am constantly expanding my knowledge to innovate and lead effectively. My journey is driven by a commitment to excellence, and to make a meaningful impact in the world.
India Orthopedic Devices Market: Unlocking Growth Secrets, Trends and Develop...Kumar Satyam
According to TechSci Research report, “India Orthopedic Devices Market -Industry Size, Share, Trends, Competition Forecast & Opportunities, 2030”, the India Orthopedic Devices Market stood at USD 1,280.54 Million in 2024 and is anticipated to grow with a CAGR of 7.84% in the forecast period, 2026-2030F. The India Orthopedic Devices Market is being driven by several factors. The most prominent ones include an increase in the elderly population, who are more prone to orthopedic conditions such as osteoporosis and arthritis. Moreover, the rise in sports injuries and road accidents are also contributing to the demand for orthopedic devices. Advances in technology and the introduction of innovative implants and prosthetics have further propelled the market growth. Additionally, government initiatives aimed at improving healthcare infrastructure and the increasing prevalence of lifestyle diseases have led to an upward trend in orthopedic surgeries, thereby fueling the market demand for these devices.
Cracking the Workplace Discipline Code Main.pptxWorkforce Group
Cultivating and maintaining discipline within teams is a critical differentiator for successful organisations.
Forward-thinking leaders and business managers understand the impact that discipline has on organisational success. A disciplined workforce operates with clarity, focus, and a shared understanding of expectations, ultimately driving better results, optimising productivity, and facilitating seamless collaboration.
Although discipline is not a one-size-fits-all approach, it can help create a work environment that encourages personal growth and accountability rather than solely relying on punitive measures.
In this deck, you will learn the significance of workplace discipline for organisational success. You’ll also learn
• Four (4) workplace discipline methods you should consider
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RMD24 | Debunking the non-endemic revenue myth Marvin Vacquier Droop | First ...BBPMedia1
Marvin neemt je in deze presentatie mee in de voordelen van non-endemic advertising op retail media netwerken. Hij brengt ook de uitdagingen in beeld die de markt op dit moment heeft op het gebied van retail media voor niet-leveranciers.
Retail media wordt gezien als het nieuwe advertising-medium en ook mediabureaus richten massaal retail media-afdelingen op. Merken die niet in de betreffende winkel liggen staan ook nog niet in de rij om op de retail media netwerken te adverteren. Marvin belicht de uitdagingen die er zijn om echt aansluiting te vinden op die markt van non-endemic advertising.
The world of search engine optimization (SEO) is buzzing with discussions after Google confirmed that around 2,500 leaked internal documents related to its Search feature are indeed authentic. The revelation has sparked significant concerns within the SEO community. The leaked documents were initially reported by SEO experts Rand Fishkin and Mike King, igniting widespread analysis and discourse. For More Info:- https://news.arihantwebtech.com/search-disrupted-googles-leaked-documents-rock-the-seo-world/
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1. Chapter-1
INTRODUCTION
1.1 Introduction to fast dispersible tablets:
Tablet is the most popular among all dosage forms existing today because of its
convenience of self administration so oral drug delivery has been known for decades as the
most widely utilized routes of administration among all the routes that has been explored for
systemic delivery of drugs via various pharmaceutical products of different dosage forms.
Dysphagia is the common problem encountered in all age groups in concern to solid dosage
forms. To solve this problem and improve patient compliance, fast dispersible tablets have
emerged as an alternative to the conventional oral dosage forms.
In the present work, fast dispersible tablets of aceclofenac were designed with
a view to enhance patient compliance by direct compression method. In the direct
compression method, crospovidone (2-9% w/w),croscarmellose sodium (2-9% w/w),
sodium starch glycolate(2-9% w/w) alone and in combination as super disintegrents were
used along with directly compressible microcrystalline cellulose to enhance mouth feel.
The prepared batches of tablets where evaluated for hardness, friability, drug content,
wetting time, water absorption ratio and invitro dispersion time. Based upon the invitro
dispersion time all formulations were tested for invitro drug release pattern in phosphate
buffer.
Keywords: Crospovidone; Croscarmellose sodium; Sodium starch glycolate.
Oral administration is the most popular routes due to ease of ingestion, pain
avoidance, versatility, and the most important patient compliance. Also solid oral delivery
systems do not require sterile conditions and therefore less expensive to the manufacturer.
Several novel technologies for fast dispersible have recently become available to address the
physicchemical an d pharmacokinetic charecteristics of a drug while improving patient
compliance.
The most desirable formulation for the use by the elderly is one that easy to swallow
and easy to handle. Taking these requirements into consideration attempts have been made to
develop a fast dispersible tablets. Since such a tablet disintegrate only a small amount of
water in the oral cavity, it is easy to take care for any age patient, regardless of time. Recently
many companies have researched and developed various types of fast disintegrating dosage
form technologies with the potential to accommodate various physicochemical,
pharmacokinetic, pharmacodynamic characteristic of drugs.
These tablets are called as fast dispersible tablets, quick disintegrating tablets, fast
disintegrating tablets, fast dissolving tablets. However, of all the above terms,
United states of pharmacopoeia(USP) approved these dosage forms.
1
2. Exhibit low sensitive to environmental conditions as temperature and humidity.
Allow the manufacturer of tablets using convinential processing and packaging.
Ease of administration to the patient who cannot swallow, such as the elderly,
stroke victims, bedridden patients, patient affected by renal failure and patient who
refuse to swallow such as pediatric, geriatric and psychiatric patients. No need of water to
swallow the dosage form, which is highly convenient feature for patients who are traveling
and do not have immediate access to water. Rapid dissolution and absorption of the drug,
which will produce quick onset of action.
NSAID posses good anti inflammatory, analgesics and anti-pyretic, used for treatment
of osteoarthriritis, rheumatoid arthritis, dental pain and other rheumatoid disorder. The major
mechanism of action of NSAID’s is prostaglandins, prostacyclins and thromboxin are
produced from archidonic acid by the enzyme cyclo-oxygenase which exits in a constutlive
(cox -1) and an inducible (cox-2) isoforms ; the formers physiological housekeeping
functions , while the later normaly present in minute quantities is induced by cytokines and
other signal molecules at the site of inflammation.
AIM :-
The aim of present work was to show the effect of various super disintegrants on
disintegration time and invitro drug release rate. In this study an attempt has been made to
prepare fast dispersible tablets of drug using different super disintegrants following
granulation and direct compression method.
The sodium starch glycolate, cross carmellose sodium and starch were used in different
concentration according to the simplex lattice design as super disintegrants.
The tablets were evaluated for diameter, thickness, hardness, friability, weight variation,
wetting time, percentage of water absorption.
1.2 OBJECTIVES OF THE STUDY
In the present study, an attempt was made to develop fast dispersible Tablets of
NASAID and to investigate the effect of super disintegrants on the release profile of the drug
from the tablets.
In order to fulfill the aim, the following objectives have to be met:
Selection of suitable super disintegrants to develop the dosage form based on
physicochemical properties of NASAID and excipients.
Selection of suitable technology for preparing fast dissolving tablets.
Screening of excipients for compatibility and efficacy for developing the formulation.
Evaluation of compressed products and identification of compression defects.
To evaluate the stability of the prepared formulations as per ICH guidelines.
2
3. 1.3 Choice of Drug Candidate
Suitable drug candidate for fast dispersible tablet should posses:
No bitter taste.
Good stability in water and saliva.
Dose should be low as possible.
Unsuitable drug candidate for orally disintegrating tablet should include:
Short half-life and frequent dosing.
Drug having very bitter taste.
Required controlled or sustained release.
3
5. Chapter -3
REVIEW OF LITERATURE
Sumanta et al12., formulated fast dispersible tablet of Aceclofenac by using
superdisintegrants such as crospovidone and sodium starch glycolate. Stability studies
indicated that tablets containing superdisintegrants were sensitive to high humidity conditions
and fast dispersible tablet of aceclofenac could be prepared by direct compression method.
Senoy et al13., fast dissolving tablets of diclofenac sodium was developed by using
direct compression after incorporating super disintegrants such as Cross linked Carboxy
Methyl Cellulose, Sodium Starch Glycolate and Cross linked povidone in different
concentrations and evaluated the effect of their concentrations on the characteristics of fast
dissolving tablets mainly in terms of disintegration time and dissolution rate. Tablets
containing cross linked Carboxy Methyl Cellulose showed better disintegrating character
along with rapid release.
Mallikarjuna et al14., developed fast dispersible tablet of aceclofenac by direct
compression method. In this method, they have studied effect of superdisintegrants such as
croscarmellose sodium, sodium starch glycolate and crospovidone. From the data obtained it
can be concluded that disintegration time and dissolution parameters decreased with increase
in the level of croscarmellose sodium and increased with increase in the level of sodium
starch glycolatein tablets and crospovidone dependent on the aggregate size in the dissolution
medium.
Anupamakalia et al15., developed fast dissolving tablets of oxcarbazepine to provide
immediate relief from epilepcy. Hence, the present investigation was undertaken with a view
to develop mouth-dissolving tablets of oxcarbazepine, which offers a new range of product
having desired characteristics and intended benefits. In this study, the mouth dissolving
tablets were prepared using two different technologies, direct compression method and solid
dispersion technology.
5
6. Raghavendrarao et al16., developed rapidly disintegrating tablets of carbamazepine,
which is a bitter drug poor solubility in biological fluids is the major problem with this drug
has also its poor bioavailability after oral administration. The rate of absorption or the extent
of bioavailability for such a poor soluble drug is controlled by rate of dissolution in GIT
fluids. Hence, to enhance the solubility of the drug a complex of carbamazepine was prepared
with β-cyclodextrin and this complex was compressed into tablets.
Suryakanta et al17., formulated a fast dissolving tablet of salbutamol sulphate to
improve the onset of action of bronchodilator for the treatment of asthma. The tablets were
prepared by direct compression method using superdisintegrants such as explotab,
microcrystalline cellulose, Ac-Di-Sol and ammonium bicarbonate. The prepared tablets were
evaluated for weight variation, thickness, friability, hardness, drug content, in vitro
disintegration and in vitro drug release. Among all the formulation ammonium bicarbonate
showed the least disintegration time.
Ganesh kumar et al18., prepared fast dissolving tablets of chlorpromazine HCl in the
oral cavity with enhanced dissolution rate. The tablets were prepared with five super
disintegrants eg: Sodium starch glycolate, Crospovidone, Croscarmellose, L-HPC,
Pregelatinised starch, The blend was examined for angle of repose, bulk density, tapped
density, compressibility index and Hausners ratio. The tablets were evaluated, It was
concluded that the fast dissolving tablets with proper hardness, rapidly disintegrating with
enhanced dissolution can be made using selected superdisintegrants.
Nilesh et al19., compared the effect of superdisintegrants and subliming agent on the
fast dissolving property of lansoprazole tablets. Orodispersible tablets of lansoprazole were
prepared using camphor and ammonium bicarbonate as subliming agent and sodium starch
glycollate, crosscarmellose sodium as superdisintegrants. Primarily powder blend and
granules were evaluated for preformulation parameters. The formulations were evaluated for
weight variation, hardness, friability, drug content, water absorption ratio, wetting time, in
vitro dispersion, in vitro disintegration and in vitro dissolution.
Ravi Kiran et al20., orodispersible tablets of piroxicam were prepared using two
different superdisintegrants namely crospovidone and sodium starch glycolate with two
concentrations (3% and 5%) and a control (without superdisintegrant) by direct compression
method. The final blend of the drug and excipients were evaluated for powder flow
properties, bulk density, tapped density, compressibility index and hausner’s ratio. All the
6
7. formulations were evaluated for thickness, weight variation, disintegration time, hardness,
friability, drug content and water absorption ratio. Formulation F1 showed the lowest
disintegration time and more water absorption ratio. invitro dissolution studies revealed that
formulation F2 showed 93.70 % percent drug release at the end of 60 minutes. The short term
stability studies for the formulations showed no significant changes in disintegration time,
drug content and percentage of drug released when stored at 40C±20◦C, 27°C ±2°C and
45◦C±20◦C for 45 days.
3.1 DRUG PROFILE:
Aceclofenac is a new phenylacetic acid derivative provided with marked
antiinflammatory, antiarthritic, analgesic and antipyretic activities in animal experimental
models.
IUPAC Name Aceclofenac
2-[2-[2-(2,6-Dichlorophenyl)aminophenyl]acetyl]oxyacetic
Synonyms
acid
Molecular Structure
Molecular Formula C16H13Cl2NO4
Molecular Weight 354.19
CAS Registry Number 89796-99-6
Properties
Melting point 149-153 º
7
8. PHARMACOKINETIC STUDY:
BIOAVAILABILITY:
PROTEIN BINDING:
ROUTES OF ADMINISTRATION:
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
Pregnancy Category : Category N
Aceclofenac has been shown to have potent analgesic and anti-inflammatory
activities, similar to indomethacin and diclofenac due to its preferential cox-2 inhibitor, it has
better safety than conventional NSAIDs with respect to the adverse effect on gastrointestinal
and cardiovascular system.
INTRODUCTION
The pain is symptomatic of some form of dysfunction and resultant inflammatory
processes in the body. A survey conducted for the WHO reported that one adult in five
suffers from chronic non-malignant pain, which mostly occurs in the back, head, joints and
limbs. More than 15% of the worldwide population suffers for instance from some form of
osteoarthritis, and this incidence is even higher in the elderly. As the world population is
grows older, this incidence will continue to rise.
The pain has been defined as a characteristic sensation arising from a noxious
stimulus, which includes its neurophysiological aspect. Sherrington, in his classic definition
has further included the reactive component of pain, i.e. the "psychical adjuvant of an
imperative protective reflex". This indicates that pain also has a survival value for the
species. There are two main classes of pain superficial and deep. Some pain receptors in the
8
9. body are probably chemoreceptors, as a wide variety of compounds, including autacoids like
bradykinin, and several of the prostaglandins, can elicit the pain. Drugs can alter the pain
experience in three ways (Pain reception, perception, and reaction) the first that can be
intercepted is peripheral pain reception at the nerve endings. This modality is susceptible to
non-narcotic analgesic and local anesthesia. The second step, which can be modified, is pain
perception at the level of the CNS. Both, narcotic and non-narcotic analgesics interfere with
this level of pain integration. The third step, which can be influenced, is pain reaction.
Mechanism of pain & Inflammation:
Prostaglandins are implicated in the inflammatory response and are sensitizing
nociceptors to the actions of other Mediators, occurring during acute and chronic
inflammatory illness, prostaglandins are produced at the site of inflammation where it is
believed that they mediate many of symptoms of inflammation such as oedema and pain.
Arachidonic acid is released from cell membranes by phospholipases,
cyclooxygenases catalyze the addition of molecular oxygen to arachidonic acid to form in
initially the endoperoxide intermediate prostaglandin G2. The same enzymes also process
peroxidase activity, which catalyzes the reduction of these prostaglandins to form
PGH2. PGH 2 may then react with a number of enzymes sometimes called isomerases to
become one of the prostaglandins or thromboxanes.
Role of Non-Steroidal Anti inflammatory drugs in pain (NSAIDs)
Orally administered NSAIDS play an important role in symptomatic management of
osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and other acute pain conditions.
In general, they produce their anti-inflammatory and analgesic effects by inhibiting
cyclooxygenase and this preventing the production of prostaglandins from arachidonic acid.
It has been suggested that some NSAIDS inhibit leukotriene production via lipooxygenase
inhibition.
9
10. 3.2 Excipient profiles:
An excipient is generally a pharmacologically inactive substance used as a carrier for
the active ingredient of a medication. In many cases, an "active" substance, may not be
easily administered and absorbed by the human body; in such cases the substance in question
may be dissolved into or mixed with an excipient. Excipients are also sometimes used to bulk
up formulations that contain very potent active ingredients, to allow for convenient and
accurate dosage. In addition to their use in the single-dosage quantity, excipients can be used
in the manufacturing process to aid in the handling of the active substance concerned.
Depending on the route of administration, and form of medication, different excipients may
be used. For oral administration tablets and capsules are use
3.2.1 Sodium starch glycolate :
The superdisintegrantsPrimojel® (sodium starch glycolate) and Primellose®
(croscarmellose sodium) are cross-linked and substituted polymers of glucose.
Sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch. The molecular
weight is typically 500 000-11 000 000.
Very fine, white or off white, free flowing powder; odourless or almost odourless. Practically
insoluble in water, insoluble in most organic solvents. It consists of oval or spherical
granules, 30-100 µm in diameter with some less-spherical granules ranging from 10-35 µm in
diameter.
SSG is used as disintegrant for tablets, capsules and granules. The tablets mainly produced by
direct compression method and wet granulation method.
SSG is recommended in a concentration of 2-8% of total weight.
SSG is starch derivative which chemical and physical identities meet to the latest standards of
(Ph.Eur.,USP-NF, BP).
Characteristics
The effects of SSG as a disintegrating agent are caused by the rapid absorption of water and
enormous swelling properties of SSG particles. Undissolvable in water the swollen SSG
particles remain intact and consequently cause the rapid disruption of tablet in its
components. Hence, SSG improves the release and absorption of active ingredient. Even after
a long storage the effect of disintegration enhancement remains.
Usage of hydrophobic lubricants in the tablet formulation often reduces the disintegration time.
10
11. 3.2.2. Crosscarmellose :-
Croscarmellose sodium is an internally cross-linked sodium carboxymethylecellulose for
use as a disintegrants in pharmaceutical formulations.
Croscarmellose sodium also resolves formulators' concerns over long-term functional
stability, reduced effectiveness at high tablet hardness levels, and similar problems associated
with other products developed to enhance drug dissolution. Croscarmellose sodium is a very
commonly used pharmaceutical additive approved by the U.S FOOD AND DRUG
ADMINISTRATION. Its purpose in most tablets - including dietary supplements - is to assist
the tablet in disintegrating in the intestinal tract at the required location. If a tablet
disintegrating agent is not included, the tablet could disintegrate too slowly, in the wrong part
of the intestine or not at all, thereby reducing the efficacy and bioavailability of the active
ingredients. . As a result, it provides superior drug dissolution and disintegration
characteristics, thus improving formulas' subsequent bioavailability by bringing the active
ingredients into better contact with bodily fluids
Croscarmellose sodium is made by first soaking crude cellulose in sodium hydroxide,
and then reacting the cellulose with sodium monochloroacetate to form sodium
carboxymethylcellulose. Excess sodium monochloroacetate slowly hydrolyzes to glycolic
acid and the glycolic acid catalyzes the cross-linkage to form croscarmellose
sodium. Chemically, croscarmellose sodium is the sodium salt of a cross-linked, partly O-
(carboxymethylated) cellulose.
APPLICATIONS :
Croscarmellose sodium is used in oral pharmaceutical formulations as a disintegrant
for Capsules, Tablets and Granules.
In tablet formulations, Croscarmellose sodium may be used in both direct-compression and
wet-granulation processes.
When used in wet granulations the Croscarmellose sodium is best added in both the wet and
dry stages of the process (intra- and extra granularly) so that the wicking and swelling ability
of thedisintegrant is best utilized.
Concentrations of up to 5% w/w of Croscarmellose sodium may be used as a tablet
disintegrant although normally 2% w/w is used in tablets prepared by direct compression and
3% w/w in tablets prepared by a wet-granulation process.
11
12. STABILITY AND STORAGE CONDITIONS :
Croscarmellose sodium is a stable though hygroscopic material.
Croscarmellose sodium should be stored in a well-closed container in a cool, dry, place
3.2.3 Talc
Talc as a pure chemical compound is a hydrous magnesium silicate, [Mg6 (Si8O20)
(OH4)], that exists in sheetlike crystalline forms or as fibers. The purity and physical form of
any sample depends on the source of the talc and on the minerals found in the ore body from
which it is refined.
• The effectiveness of talc glidant activity is dependent upon particle size compatibility
between the talc and other powders in the formulation.
• Talc lubricant efficiency in plastic deforming binder/fillers increases with decreasing talc
particle size and increasing talc surface area.
• Talc improves direct compression tablet formulation disintegration behavior independent of
particle size.
• Talc can effectively be used in combination with magnesium stearate to restore
disintegration and dissolution properties impaired by magnesium stearate.
3.2.4 Microcrystalline cellulose:
Micro Crystalline Cellulose is a mechanically disintegrated level of D.P. Cellulose. It
comprises purified, de-polymerised, Micro Crystalline sub micron size colloidal particles. It
is produced by treating Alfa Cellulose obtained as a pulp from fibrous plants with minerals
acid.
It is a white, odourless, tasteless, extra free flowing powder which is relatively free
from organic and non-organic contaminants. It is metabolically inert, and has excellent water
absorptive, swelling & dispersion properties, is insoluble in water, dilute acid, common
organic solvents and oils. It is partially soluble in dilute alkali.
12
13. Direct Compressible Grade of Micro Crystalline cellulose performs as an excipient to assist
in the flow, lubrication and binding properties of the ingredients to be tableted and improves
stability of durgs. Facilitate rapid disintegration of the tablet.
It can be used in direct compression of most drugs and because of savings in material, capital,
equipment and labour, it compensates the higher price of Direct Compressible Micro
Crystalline Cellulose over non spray dried Micro Crystalline Cellulose.
The conventional costly method of tableting through 6 process steps is replaced by 2 steps
direct compression method of tableting.
Detailed tests and investigations by various agencies for the use of Direct Compressible
Grade Micro Crystalline Cellulose powder in tableting have shown:
a. Excellent Compression & Hardness
b. No Sign of Lubrication Difficulties
c. Good Flowing Properties
d. Reduces Friability & Weight Loss
3.2.5 Mannitol:
Mannitol is a white, crystalline organic compound with the formula (C6H8(OH)6).
Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals
directly into the brainMannitol is a polyol (sugar alcohol) and an isomer of sorbitol. Mannitol
(C6H8(OH)6) is used in pharmaceutical products as a sweeting agent, tablet and capsule
diluent, excipient for chewable tablets, a tonicity agent, and as a vehicle (bulking agent) for
lyophilized preparations. Mannitol is industrially derived from the sugar fructose, and is
roughly half as sweet as sucrose. Mannitol has a cooling effect often used to mask bitter
tastes, and may be used in gums and candies. Mannitol is also found naturally in many
species, including plants, bacteria, and fungi.
3.2.6 Starch:
Maize, potato, rice and tapioca (cassava) starch were evaluated with respect to their
properties on direct compression. Rice starch showed much better compactibility as
compared to maize, potato and tapioca starch. Moreover, its binding capacity proved to be
almost insensitive to mixing with magnesium stearate.
13
14. Starch is also utilized in pharmaceuticals and cosmetics. Starch derivatives often have special functions in
tablets: they act as a disintegration aid.Specially modified starch derivatives give tablets good stability,
provide low abrasion and stable consistency. In moistened condition, i.e. during oral intake the starches
swell heavily. This accelerates the disintegration the tablet and finally leads to the liberation of the effective
substance. Further applications in pharmacy include starches for the production of hard and soft capsules as
well as highly purified starch derivatives as basic material for the production of blood plasma substitutes.
In the field of cosmetics, starch is added to creams, powders, and shower gels to impart special properties to
the products. They for instance generate a more comfortable and velvety feeling on the human skin.
Furthermore, highly modified products are used as a lubricant for latex products (gloves and condoms).
The following test procedures are available:
Analytical characterisation of starch derivatives
Production and testing of tablets
Testing of tactility of cosmetic products
Determination of cooking strength
Checking stability of multiphase systems
Further examples for the application of starch in special fields are:
Flocculating aid for ceramics
Flocculating agent for wastewater treatment
Additives for drilling fluids
Emulsifier for emulsion polymerisation
Paints and varnishes
Packaging material (foils and padding material)
Binding agent for foundry
Basic material for the production of chemicals
Biopolymers
Starch is one of the most widely used excipients in the manufacture of solid dosage forms. Starches
from different sources have been evaluated and used as excellent binders in either mucilage or the
drypowdered form Although maize starch is the most frequently used excipient in tabletting, researchers
have tried to develop botanical starches for use tablet excipient. Preliminary these starches following official
and un-official protocols showed that they posses some of the desirable features of good excipient.
14
15. 3.2.7 Magnesium stearate:
Magnesium stearate is often used as a diluent in the manufacture of medical tablets,
capsules and powders. In this regard, the substance is also useful, because it has
lubricating properties, preventing ingredients from sticking to manufacturing equipment
during the compression of chemical powders into solid tablets; magnesium stearate is the
most commonly used lubricant for tablets. Studies have shown that magnesium stearate may
affect the release time of the active ingredients in tablets, etc., but not that it reduces the
overall bioavailability of those ingredients. As a food additive or pharmaceutical excipient, its
E number is E470b.
Magnesium stearate is also used to bind sugar in hard candies and is a common ingredient in
baby formulas. In pure powder form, the substance can be adjust explosion hazard, although
this issue is effectively insignificant beyond the manufacturing plants using it.
Magnesium stearate is manufactured from both animal and vegetable oils. Some nutritional
supplements specify that the magnesium stearate used is sourced from vegetables.
Magnesium stearate is a major component of "bathtub rings." When produced by soap and
hard water, magnesium stearate and calcium stearate both form a white solid insoluble in
water, and are collectively known as soap scum.
Magnesium stearate is created by the reaction of sodium stearate with magnesium sulfate.
Formulations F1-F3
Ingredients (mg) F1 F2 F3
Aceclofenac 100 100 100
SSG 30 25
CCS 30
Starch 15 15 15
Mg.sterate- 5 5 5
Mannitol- 50 50 50
MCC -- --- 25
SSG = Sodium starch glycolate
CCS = Cross carmellose sodium
MS = Magnesium stearate
Mcc=microcrystalline cellulose
SS = Sodium saccharin
F= Formulatio
15
16. Chapter - 4
Methods of formulation development
4.1 Preformulation studies
Preformulation is defined as the phase of research and development process where
physical, chemical and mechanical properties of a new drug substance are used alone and when
combined with excipient inorder to develop stable ,safe and effective dosage form.A through
understanding of physicochemical properties may ultimately provide a rationale for formulation
design, or support the need for molecular modification or merely confirm that there is no
significant barrier to the formulation development. A stage of development during which the
physicochemical properties of drug substance are characterized.
• Some commonly evaluated parameters:
a. Solubility.
b. Dissolution behaviour.
c. Stability.
d. Partition coefficient.
e. Ionization constant (pKa).
f. pH-Solubility Profile and Effect of Temperature.
Solid state properties such as crystal forms/polymorphs, water sorption behavior, surface
properties, particle size and shape, and other mechanical properties.
Solubility:
Practically insoluble in water, freely soluble in acetone, soluble in alcohol.
IDENTIFICATION
Dissolve 50.0 mg in methanol R and dilute to 100.0 ml with the same solvent. Dilute
2.0 ml of the solution to 50.0 ml with methanol R. Examined between 220 nm and 370
nm (2.2.25), the solution shows an absorption maximum at 275 nm. The specific absorbance
at the maximum is 320 to 350.
Dissolve about 10 mg in 10 ml of alcohol R. To 1 ml of the solution, add 0.2 ml of a
mixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassium
ferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from light
for 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protected
from light for 15 min. A blue colour develops and a precipitate is formed.
Stability studies:
1.Chemical stability studies
16
17. Solid state stability
Effect of moisture
Effect of solid state form – amorphous vs. crystalline
Excipient compatibility
Effect of moisture
Effect of processing
2.Degradation mechanism
Hydrolysis
Oxidation potential
Effect of temperature
3.Physical stability studies
Effect of moisture on drug
Solid solubility
Characterization of hydrates/solvates
Effect of processing
Impact on chemical stability and bioavailability.
4.Some Practical Considerations in Salt Screening and Selection
Dosage Form Considerations
IV vs. oral formulations
High dose vs. low dose
Excipient compatibility
Interaction with other actives in potential combination formulations
Salts and Other Solubilization Techniques
Effect of Salts on Complexation Binding Constants
Effect of Salts on Solublization by Surfactants
Solubility of Salts in Non-aqueous Solvents
Toxicological Considerations
4.2 Formulation development
4.2.1 Granulation techniques
Granulation process has been widely used in the pharmaceutical industry
for the preparation of material for tabletting. Other process which involves the granule
formation includes microencapsulation, multi-particulate system for modified release
mechanism and to prepare granules to be used by patient directly.
Primarily granules are prepared to improve flow and compression characteristics of
the blend but there are many other reasons and some times multiple reasons for
granulation such as-
17
18. • Improving flow properties of the mix and hence the uniformity of the dose
• Increasing the bulk density of a product
• Facilitating metering or volumetric dispensing
• Controlling the rate of drug release
• Decrease dust generation and reduce employee exposure to drug product
• Improving product appearance
What is Granulation..?
Granulation may be defined as a size enlargement process which converts fine or
coarse particles into physically stronger and larger agglomerates having good flow property,
better compression characteristics and uniformity. The art and science for process and
production of granules is known as Granulation Technology.
Granulation Technology can be broadly classified into 2 types based upon the type of
processing involved.
1. Wet granulation method and
2. Dry granulation method.
4.2.1 Wet granulation method:
Wet granulation is a pharmaceutical unit operation whereby a liquid or binder solution
is sprayed onto a powder blend to improve the flow, compressibility, and content uniformity
of the blend, prior to tabletting.
Improvement of flow and compressibility can be important in extended/controlled release
matrix formulations where polymers with fine particle size are typically utilized to ensure
rapid, reproducible polymer by Wet Granulation
Wet granulation is the most widely used process of granulation in the pharmaceutical
industry.
It involves addition of a liquid solution (with or without binder) to powders, to
form a wet mass or it forms granules by adding the powder together with an
adhesive, instead of by compaction . The wet mass is dried and then sized to obtained
granules. The liquid added binds the moist powder particles by a combination of
capillary and viscous forces in the wet state. More permanent bonds are formed during
subsequent drying which leads to the formation of agglomerates.
Although the process is most widely used in the pharmaceutical industry, the
conventional wet granulation process has following merits and demerits.
18
19. Merits and Demerits of conventional Wet Granulation Process
Merits :-
a. It improves and flow properties and expensive because of labour,
compression characteristics and special equipment and increases
density of granules.
b. It reduces dust hazards.
c. It prevents segregation of powders.
d. It makes hydrophobic surfaces and hydrophilic.
e. Better distribution of colour and processing steps involved in soluble
drugs if added in binding add complexity.
Demerits :-
a. Process requires more space, time and energy requirement.
b. Multiple the process.
c. Loss of material during the various stages of processing.
d. Moisture sensitive and drugs are poor candidates.
e. Any incompatibility between the formulation component is aggravated
during the processing.
Process details:
conventional wet granulation
According to Iveson there are fundamentally only three stages of process, which
determines the wet agglomeration behaviour:
• Wetting and nucleation;
• Consolidation and growth and finally
• Breakage and attrition.
19
20. Figure illustrates the granule growth phenomenon
These phenomena often take place simultaneously in the granulation equipment,
making the investigation of the effect of an individual phenomenon on the agglomerate
properties difficult. Wetting of the articles is necessary for nucleation, i.e. the formation
of initial agglomerates. As per Hapgood the nucleation rate is governed by following-
• Wetting thermodynamics
• Drop penetration kinetics and
• Binder dispersion.
“The binder dispersion in the powder mass depends on the liquid delivery
parameters and powder mixing.”
Since wet granulation method is the oldest and most convention method of
making granules, all components involved in this process forms a three phase system made
of:
• Dispersed solid
• Granulation liquid and
• Air.
Cohesive Force that operates during the moist agglomeration process is mainly
due to the liquid bridges that develop between the solid particles, even though
20
21. intermolecular attractive forces, van der waals forces and electrostatic forces also play an
initial role.
States of liquid content during wet granulation
When liquid is added to the drug powder during initial stage, liquid film is formed
on powder surface. Discrete liquid bridges are then built at the point of contact. This
state is termed as Pendular State, surface tension and the capillary provide the cohesive
force during this stage, air is still present between the particles. As the liquid content
increases air starts coalesce. The strength of the blend increases. In this so called
Funicular State, the air does not built a coherent phase anymore. As water content
increases further all inter-particle voids are filled.
Capillary pressure and interfacial forces at granule surface hold the particles at this
stage called Capillary State. Granules attain its maximum strength at this stage. Further
addition of liquid, forms solid particles, completely surrounded by the liquid, resulting
in the droplet State. During this stage system consist only two phases, dispersed solid
and liquid phase. When the granulation process is finished, the liquid is removed by
drying, after that the granule is still kept together by different bonding
mechanismsdration.
21
22. 4.2.1.2 Dry granulation method:
In order to obtain the desired granules, the compaction process is followed by a milling step.
PROCESS BASICS
Principally there are two methods to obtain the compacts when using dry granulation:
slugging and roller compaction.
Slugging
If a tablet press is used for the compaction process, the term slugging is used. But
since particles with a small particle size do not flow well into the die of a tablet press, the
results are weight differences from one tablet (slug) to another. This in turn causes large
fluctuations in the forces applied onto the individual slugs, with translates in variations of the
slug’s mechanical strength. Therefore, the properties of these granulates obtained by milling
the slugs cannot be controlled well either.
This is one of the main reasons why slugging is hardly used any more as a dry granulation
method.
Roller Compaction
A GERTEIS® Roller compactor generally consist of three major units:
1. A feeding system, which conveys the powder to the compaction area between the rolls
2. A compaction unit, where powder is compacted between two counter rotating rolls to a
ribbon by applying a force
3. A size reduction unit, for milling the ribbons to the desired particle size.
1.Inlet funnel with agitator
2.Feed auger
22
23. 3.Tamp auger
4.Small quantity inlet funnel
5.Press rolllers with ribbon
6.Rotor with desired granules
PRODUCT QUALITY ASPECTS
Process Parameters: Force and Gap
The powder is compacted between two rolls by applying a force, which is the most
important parameter in the dry granulation process. The applied force is expressed in kN/cm,
being the force per cm roll width. Occasionally the press force is also indicated in bar. This,
however, merely represents the pressure within the hydraulic system, and is in fact not an
appropriate measuring unit for the force applied onto the powder.
At a given force, depending on the amount of powder conveyed to the rolls, the powder will
be compacted to a predefined ribbon thickness.
A precise process control is essential to obtain equal granules properties from a homogenous
ribbon. For more on that topic see section PAT below.
Variable and Fixed Gap Roller Compactors
Roller compactors can be divided into two categories: One is equipped with a fixed
gap, the other one with a floating gap. Both consist of the three major units as explained
above but differ in the way in which the smallest distance (gap) between the rolls is realized.
When a fixed gap is installed, the amount of powder drawn in into the compaction area
between the rolls is inconsistent, which results in different forces applied to the powder bed.
Like in slugging, this will cause large fluctuations in the ribbon and granulate properties.
With floating gap (e.g. GERTEIS®-Machines) the distance between the rolls change
according to the amount of powder provided. The force applied to the powder remains
constant. This ensures that property fluctuations in the granules are reduced to a minimum.
Milling
With our integrated models, the ribbons are being milled right after compaction using a
screen with a given mesh size, thus limiting the upper particle size.
This milling process should be performed as gently as possible, so as to avoid creating too
many fines.
PAT (= Process Analytical Tool)
The GERTEIS® roller compactors are able to control and measure all product quality
relevant parameters (e.g. force, gap and roll speed) on-line in order to fulfill the requirements
of the pharmaceutical industry for a well controlled and documented manufacturing process.
All the parameters are calibrated and validated. Additionally, in order to cope with batch to
23
24. batch variations, our machines are fitted with control systems to allow equal granule
properties during manufacturing according to PAT.
APPLICATIONS
Improving Flow Ability
Dry granulation is used for increasing the bulk density of powders, whilst increasing
the particle size, resulting in better flowing material, which is a prerequisite for
manufacturing capsules and tablets on high speed production equipment.
Furthermore, bonding the particles of various substances together during the compaction
process reduces the tendency to segregation of powder particles of different substances. This
results in an improvement of the homogeneity of the active ingredients (API) within the
powder blend, causing an improvement of dose uniformity of such dosage forms.
Wet- & Dry Granulation
In contrast to wet granulation, dry granulation is a continuous process. This results in various
economical advantages. Nowadays the throughput of common dry granulation systems can
reach 400kg/h. Dry granulation systems require comparatively fewer investments into
buildings or equipment. Coupled with lower maintenance costs, this results in a much higher
overall profit.
5. Evaluation studies:
5.1 INVITRO dissolution studies by using USP PADDLE apparatus:
Preparation of phosphate buffer of ph 6.8:
Weigh 27.22gms of monobasic potassium phosphate (KH2PO4) and dissolved in 100ml to get
stock solution of 0.2m potassium dihydrogen phosphate.weighed 8gms of NaOH dissolved in
1000ml to get 0.2m NaOH solution.
50ml of monobasic potassium phosphate solution from stock solution was taken in a200ml
volumetric flask, 22.4ml of NaOH solution from stock solution of 0.2m NaOH solution was
added, and then water to volume was added.
Procedure for dissolution study:
After preparation of phosphate buffer it is transferred into 900ml into a
basket.Now set rpm to 50 and now adjust the temperature to 37.5 degree centigrades.
After reaching the desired temperature now drop the tablet into phosphate buffer and it is
runned for dissolution. Now collect the sample of 2ml for 10mins and it is filterd through
sintered glass filter and now immediately replace 2ml of fresh buffer solution.Now 1ml of
filtered solution is diluted to 100ml with distilled water.Repeat the same procedure for
20mins,30mins,40mins,50min,and 60mins and measure the released drug concentration by
using uv/visible spectrometer at 274nm.
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