LAPORAN AKHIR

PRAKTIKUM FORMULASI DAN TEKNOLOGI SEDIAAN PADAT

PREFORMULASI BISOPROLOL FUMARATE

KOORDINATOR PRAKTIKUM
Apt. Wintari Taurina, M.Sc.
NIP.198304212008012007

ASISTEN PRAKTIKUM
Sitti Mukkaromah
NIM. I1021171001

DISUSUN OLEH
Nuha Salwa Alifa Putri
NIM. I1021191012

KELOMPOK / KELAS : 5 / Regular A

ANGGOTA : Ayu Setyaningrum (I1021191015)
Sinta Selvia (I1021191021)
Agustina Jesica (I1021191031)
Nabila Nuraini (I1021191038)
Fina Ari Ibah (I1021191045)
Bella Christin (I1021191055)
Verdi Ardianto (I1021191060)
Natalia Christie (I1021191063)
Rizki Mutia Sari (I1021191065)
Fiqri Muhammad (I1021191076)
Laila Kamilia (I1021191080)
Syarifah Elvina Febriana Alkadrie (I1021191085)
Salsa Nabila Awlia (I1021191093)

LABORATORIUM TEKNOLOGI FARMASI

PROGRAM STUDI FARMASI
FAKULTAS KEDOKTERAN
UNIVERSITAS TANJUNGPURA
PONTIANAK
2021
 LEMBAR PENGESAHAN
LAPORAN PRAKTIKUM FORMULASI & TEKNOLOGI
SEDIAAN PADAT

Saya yang bertanda tangan dibawah ini :

Nama : Nuha Salwa Alifa Putri

NIM : I1021191012
Judul Praktikum : Preformulasi Tablet Bisoprolol Fumarate
Tanggal Praktikum : Selasa, 23 Februari 2021
Asisten praktikum : Siti Mukkaromah

Menyatakan dengan sebenarnya bahwa laporan praktikum praktikum

formulasi & teknologi sediaan padat ini benar-benar merupakan hasil tulisan saya
sendiri dan dibuat berdasarkan data yang sebenar-benarnya. Apabila dikemudian
hari terbukti atau dapat dibuktikan bahwa ini bukan tulisan saya atau hasil plagiat,
saya bersedia menerima sanksi atas perbuatan tersebut.

Pontianak, 23 February 2021

Asisten Praktikum Praktikan,

Siti Mukkaromah Nuha Salwa Alifa Putri

NIM. I1021171001 NIM. I1022191012
 BAB I
PENDAHULUAN
I.1 Latar Belakang
Preformulasi adalah langkah pertama dalam perumusan suatu bahan
aktif dalam farmasi. Properti mikromeritik merupakan hal yang harus diteliti
seperti densitas bongkahan, densitas kempa, indeks kompresibilitas dan
analisa ayakan untuk menentukan eksipien terbaik dalam pembuatan sediaan.
Zat aktif harus diketahui sifat alirnya untuk mengetahui proses pembuatannya
(Migoha, 2015).
Tablet adalah sediaan padat kompak, dibuat secara kempacetak, dalam
bentuk tabung pipih atau sirkuler, kedua permukaannya rata atau cembung,
mengandung satu jenis obat atau lebih dengan atau tanpa zat tambahan. Zat
tambahan yang di gunakan dapat berfungsi sebagai zat pengisi, zat
pengembang, zat pengikat, zat pelicin, zat pembasah, atau zat lain yang cocok
(FI III, 1997). Tablet terdapat dalam berbagai bentuk, ukuran, bobot,
kekerasan, ketebalan, sifat solusi dan disintegrasi tergantung tujuan
penggunaannya. Sediaan tablet juga terbukti menunjukkan suatu kelebihan
berupa bentuk yang efisien, sangat praktis dan ideal untuk pemberian zat aktif
secara oral (Murtini, 2018).
Pentingnya mengetahui preformulasi dalam bidang farmasi adalah agar
memahami karakterikstik sediaan dan zat yang belum diketahui. Proses
pembuatan tablet juga penting dalam preformulasi agar tidak terjadi kesalahan.
Zat aktif yang digunakan juga penting agar tidak salah menentukan bahan
tambahan yang digunakan (Migoha, 2015).

I.2 Tujuan
Tujuan dari praktikum ini adalah untuk mengetahui pertimbangan
bahan pengisi untuk formulasi tablet pelepasan segera berdasarkan studi
pelepasan obat (1).
 BAB II
TINJAUAN PUSTAKA
II.1 Monografi Bahan
II.1.1 Bisoprolol Fumarat(4)(5)(6)(7)
Struktur

Rumus Molekul (C18H31NO4)2.C4H4O4

Berat Molekul 766,96
Pemerian Serbuk putih atau hampir putih, agak higroskopis.
Sangat mudah larut dalam air dan dalam metanol;
mudah larut dalam kloroform, dalam asam asetat
Kelarutan
glasial dan dalam alkohol; sukar larut dalam
aseton dan dalam etil asetat.
Khasiat Memiliki efek menurunkan tekanan darah
sistolik.
Inkompatibilitas -
Penyimpanan Dalam wadah tertutup rapat, tidak tembus cahaya,
pada suhu ruang.
Titik Didih 445°C di 760 mmHg
Titik Leleh 222.9°C
Berat Jenis 441.5152

II.1.2 Microcrystalline Cellulose(7)(8)

Struktur
 Rumus Molekul (C6H10O5)n
Berat Molekul 342.2965
Pemerian Kristal putih, tidak berbau, tidak berasa, bubuk
terdiri dari partikel berpori. Ini tersedia secara
komersial dalam ukuran partikel yang berbeda dan
tingkat kelembaban yang berbeda properti dan
aplikasi.
Kelarutan Sedikit larut dalam 5% b / v larutan natrium
hidroksida; praktis tidak larut dalam air, asam
encer, dan sebagian besar organik pelarut.
Khasiat Adsorben; agen penangguhan; pengencer tablet dan
kapsul; tablet disintegran.
Inkompatibilitas Microcrystalline Cellulose tidak sesuai dengan
oksidasi kuat agen.
Penyimpanan Bahan curah harus disimpan dalam wadah tertutup,
baik di tempat sejuk, tempat kering.
Titik Didih 667.9°C at 760 mmHg
Titik Leleh 260–270°C
Berat Jenis 1.512–1.668 g/cm3

II.1.3 Lactosa(8)
Struktur

Rumus Molekul C12H22O11.H2O

Berat Molekul 360.31
Pemerian Dalam keadaan padat, laktosa muncul sebagai
berbagai bentuk isomer, tergantung pada kristalisasi
dan kondisi pengeringan, yaitu a-laktosa
monohidrat, b-laktosa anhidrat, dan a-laktosa
 anhidrat.
Bentuk kristal laktosa yang stabil adalah a-laktosa
monohidrat, b-laktosa anhidrat, dan a-laktosa
anhidrat stabil.
Laktosa terjadi sebagai partikel kristal putih ke
putih pudar atau bubuk. Laktosa tidak berbau dan
rasanya sedikit manis; a-laktosa adalah kira-kira
20% semanis sukrosa, sedangkan b-laktosa 40%
semanis sukrosa manis.
Kelarutan

Khasiat Pembawa inhaler bubuk kering; bantuan liofilisasi;

pengikat tablet; tablet dan pengencer kapsul;
pengisi tablet dan kapsul.
Inkompatibilitas Reaksi kondensasi tipe Maillard mungkin terjadi di
antara keduanya laktosa dan senyawa dengan gugus
amina primer membentuk coklat, atau produk
berwarna kuning-coklat. Interaksi Maillard
memiliki juga telah terbukti terjadi antara laktosa
dan amina sekunder. Namun, urutan reaksi berhenti
dengan pembentukan imina, dan tidak ada warna
kuning-coklat yang berkembang. Laktosa juga tidak
cocok dengan asam amino, amfetamin, dan
lisinopril.
Penyimpanan Laktosa harus disimpan dalam wadah tertutup rapat
di tempat yang sejuk dan kering tempat.
Titik Didih 668,9 °C
Titik Leleh 201–202°C (untuk dehidrat α-lactosa monohidrat)
Berat Jenis 1.545 g/cm3 (α-lactosa monohidrat)
II.1.4 Magnesium Stearate(7)(8)
Struktur

Rumus Molekul C36H70MgO4

Berat Molekul 591.24
Pemerian Magnesium stearat sangat halus, putih muda,
mengendap atau bubuk yang digiling dan tidak
dapat disembuhkan dengan kepadatan curah
rendah, memiliki bau samar asam stearat dan rasa
yang khas. Bedaknya berminyak ke sentuh dan
mudah menempel di kulit.
Kelarutan Praktis tidak larut dalam etanol, etanol (95%), eter
dan air; sedikit larut dalam benzena hangat dan
etanol hangat (95%).
Khasiat Pelumas tablet dan kapsul.
Inkompatibilitas Tidak cocok dengan asam kuat, alkali, dan garam
besi. Hindari pencampuran dengan bahan
pengoksidasi yang kuat. Magnesium stearat tidak
dapat digunakan dalam produk yang mengandung
aspirin, beberapa vitamin, dan sebagian besar
alkaloid garam.
Penyimpanan Harus disimpan di tempat yang tertutup baik
dengan wadah di tempat yang sejuk dan kering.
Titik Didih -
Titik Leleh 126–130°C
Berat Jenis 1.092 g/cm3
II.1.5 Sodium Lauryl Sulfate(8)
Struktur

Rumus Molekul C12H25NaO4S

Berat Molekul 288.38
Pemerian Sodium lauryl sulfate terdiri dari warna putih atau
krem hingga berwarna kuning pucat kristal,
serpihan, atau bubuk yang terasa halus, seperti
sabun, rasa pahit, dan bau samar zat berlemak.
Kelarutan Larut bebas dalam air, memberikan larutan
opalescent; praktis tidak larut dalam kloroform dan
eter.
Khasiat Surfaktan anionik; deterjen; agen pengemulsi;
penetran kulit; pelumas tablet dan kapsul; agen
pembasahan.
Inkompatibilitas Sodium lauryl sulfate bereaksi dengan surfaktan
kationik, menyebabkan kerugian aktivitas bahkan
dalam konsentrasi yang terlalu rendah untuk
menyebabkan presipitasi. Tidak seperti sabun,
sabun ini kompatibel dengan asam encer dan
kalsium dan ion magnesium.
Sodium lauryl sulfate tidak sesuai dengan garam
polivalen ion logam, seperti aluminium, timbal,
timah atau seng, dan mengendap dengan garam
kalium. Larutan natrium lauril sulfat (pH 9,5-10,0)
bersifat korosif ringan pada baja ringan, tembaga,
kuningan, perunggu, dan aluminium.
Penyimpanan Bahan curah harus disimpan dalam wadah tertutup
baik jauh dari oksidator kuat di tempat yang sejuk
dan kering.
Titik Didih -
 Titik Leleh 204–207°C (untuk bahan murni)
Berat Jenis 1.07 g/cm3 di 20°C

II.1.6 Sodium Starch Glycolate(8)

Struktur

Rumus Molekul Sodium carboxymethyl starch

Berat Molekul -
Pemerian Sodium starch glycolate berwarna putih atau
hampir putih sangat bebas mengalir bubuk
higroskopis. PhEur 6.0 menyatakan bahwa saat
diperiksa di bawah mikroskop terlihat terdiri dari:
butiran, tidak beraturan berbentuk bulat telur atau
buah pir, berukuran 30–100 mm, atau bulat,
Berukuran 10–35 mm; butiran majemuk yang
terdiri dari 2-4 komponen terjadi sesekali; butiran
memiliki hilus eksentrik dan striasi konsentris yang
terlihat jelas. Di antara prisma nicol yang
bersilangan, butiran-butirannya menunjukkan
sebuah salib hitam yang berbeda berpotongan di
hilus; kristal kecil terlihat di permukaan butiran.
Butiran menunjukkan pembengkakan yang cukup
besar jika terkena air.
Kelarutan Praktis tidak larut dalam metilen klorida. Ini
memberi suspensi tembus cahaya dalam air.
Khasiat Penghancur tablet dan kapsul.
Inkompatibilitas Sodium Starch Glycolate tidak sesuai dengan asam
askorbat.
Penyimpanan Sodium Starch Glycolate stabil meskipun sangat
higroskopis, dan harus disimpan dalam wadah
tertutup baik untuk melindunginya dari berbagai
variasi kelembaban dan suhu, yang dapat
menyebabkan penggumpalan.
Titik Didih -
Titik Leleh Tidak meleleh, tetapi sekitar 200°C
Berat Jenis 1.56 g/cm3 untuk Primojel;
1.49 g/cm3 untuk Tablo.
 BAB III
METODOLOGI
III.1 Alat dan Bahan
III.1.1 Alat
Alat yang digunnnakan dalam praktikum ini adalah
a. Ayakan Mesh
b. Mesh 40
c. Mesin kompresi tablet rotari 8 stasiun
d. Polybag
e. Timbangan Analitik
III.1.2 Bahan
Bahan yang digunakan dalam praktikum ini adalah
a. Bisoprolol Fumarat
b. Magnesium Stearate
c. Microcrystalline Cellulose
d. Lactosa
e. Sodium Lauryl Sulfate
f. Sodium Starch Glycolate
III. 2 Cara Kerja

Ditimbang Bisoprolol Fumarat, Magnesium Stearate, Microcrystalline

Cellulose , Lactosa, Sodium Lauryl Sulfate, Sodium Starch Glycolate
yang diinginkan.

Disaring Bisoprolol Fumarat, Magnesium Stearate, Microcrystalline

Cellulose , Lactosa, Sodium Lauryl Sulfate, Sodium Starch Glycolatesatu
per satu menggunakan ayakan mesh dengan ukuran 40 mesh.

Dipindahkan semua serbuk yang telah disaring ke dalam polybag lalu

diaduk rata selama 6 menit dengan ditutup rapat.
 Dikompres campuran serbuk agar menjadi bentuk tablet dengan
menggunakan mesin kompresi tablet rotari 8 stasiun

Diletakkan tablet yang telah jadi pada wadah yang tertutup dan diberi
etiket

III. 3 Kajian Preformulasi

III.3.1 Formulasi
Kadar Fungsi/Alasan
NO Nama Bahan
(%) Penambahan Bahan
1 Bisoprolol Fumarate 200 mg Zat Aktif
Microcrystalline
2 20% Pengencer tablet
Cellulose
3 Lactose Qs Pengisi tablet
4 Magnesium Stearate 2% Lubrikan
5 Sodium Lauryl Sulfate 2% Lubrikan
Sodium Starch
6 2% Penghancur tablet
Glycolate

III.3.2 Penimbangan
Dibuat tablet Bisoprolol Fumarate 50 tablet @ 250 mg
Bobot seluruhnya : 50 𝑥 250 𝑚𝑔 = 12,5 𝑔𝑟𝑎𝑚
Bisoprolol Fumarate : 50 𝑥 200 𝑚𝑔 = 10 𝑔𝑟𝑎𝑚
a. Microcrystalline Cellulose 20%
20
𝑥 12,5 𝑔𝑟𝑎𝑚 = 2,5 𝑔𝑟𝑎𝑚
100
b. Magnesium Stearate 2%
2
𝑥 12,5 𝑔𝑟𝑎𝑚 = 0,25 𝑔𝑟𝑎𝑚
100
c. Sodium Lauryl Sulfate 2%
2
𝑥 12,5 𝑔𝑟𝑎𝑚 = 0,25 𝑔𝑟𝑎𝑚
100
d. Sodium Starch Glycolate
 2
𝑥 12,5 𝑔𝑟𝑎𝑚 = 0,25 𝑔𝑟𝑎𝑚
100
e. Lactose
𝐵𝑜𝑏𝑜𝑡 𝑠𝑒𝑙𝑢𝑟𝑢ℎ𝑛𝑦𝑎 − (𝑏𝑜𝑏𝑜𝑡 𝑚𝑖𝑐𝑟𝑜𝑐𝑟𝑦𝑠𝑡𝑎𝑙𝑙𝑖𝑛𝑒 𝑐𝑒𝑙𝑙𝑢𝑙𝑜𝑠𝑒 +
𝑏𝑜𝑏𝑜𝑡 𝑚𝑎𝑔𝑛𝑒𝑠𝑖𝑢𝑚 𝑠𝑡𝑒𝑎𝑟𝑎𝑡𝑒 +
𝑏𝑜𝑏𝑜𝑡 𝑠𝑜𝑑𝑖𝑢𝑚 𝑙𝑎𝑢𝑟𝑦𝑙 𝑠𝑢𝑙𝑓𝑎𝑡𝑒 +
𝑏𝑜𝑏𝑜𝑡 𝑠𝑜𝑑𝑖𝑢𝑚 𝑠𝑡𝑎𝑟𝑐ℎ 𝑔𝑙𝑦𝑐𝑜𝑙𝑎𝑡𝑒 = 𝑏𝑜𝑏𝑜𝑡 𝑙𝑎𝑐𝑡𝑜𝑠𝑒
250 − (2,5 + 0,25 + 0,25 + 0,25) = 246,75 𝑔𝑟𝑎𝑚
III.3.3 Alasan penambahan
NO Nama Bahan Alasan Penambahan Bahan
1. Bisoprolol Fumarate Zat aktif, merupakan golongan
obat beta bloker yang digunakan
untuk pengobatan utama penyakit
kardiovaskular.(9)
2. Microcrystalline Pengencer tablet, microcrystalline
Cellulose cellulose yang dihasilkan dari
tahapan isolasi memiliki rendemen
57,26%. Laju alir merupakan suatu
parameter penting pada pemilihan
bahan pengisi untuk tablet cetak
langsung. MCC memiliki laju alir
1,74 g/s, jika dibandingkan dengan
Avicel® PH 102 yang memiliki
laju alir 2,45g/s maka selulosa
mikrokristal memiliki lajur alir
yang lebih kecil, namun
berdasarkan Handbook of
Pharmaceutical Excipients (2009)
diketahui bahwa laju alir
Emcocel® 90M yaitu 1,41 g/s. Hal
ini menunjukan MCC maupun
Avicel® PH 102 memenuhi
 standar yang terdapat pada
literatur.(10)
3. Lactose Pengisi tablet, laktosa digunakan
untuk menjaga kekerasan tablet,
membantu memperbaiki sifat fisik
tablet, granulnya cepat kering,
hampir tidak bereaksi dengan
semua zat aktif dan laktosa
memiliki harga yang murah.(11)
4. Magnesium Stearate Lubrikan, Magnesium stearat
merupakan lubrikan yang baik
karena dapat mengurangi fraksi
antara permukaan dinding / tepi
tablet dengan dinding die selama
kompresi dan ejeksi.(12)
5. Sodium Lauryl Lubrikan, bahan pelincir berfungsi
Sulfate untuk mengurangi gesekan antara
dinding tablet dengan dinding
ruang cetak (die) pada saat tablet
ditekan keluar.(13) Bahan pelincir
yang sering digunakan adalah
asam stearat, magnesium stearat
dengan konsentrasi 0,2 - 2,0%,
PEG, kalsium stearat, natrium
stearil fumarat.(14)
6. Sodium Starch Penghancur tablet, Sodium starch
Glycolate glycolate merupakan suatu bahan
untuk mendapatkan sifat
pengembangan yang lebih baik
serta untuk meningkatkan
kecepatan disintegrasi. Kelebihan
bahan penghancur ini adalah pada
daya pengembangannya yang
sangat tinggi, dan konsentrasi yang
dibutuhkan sangat sedikit/kecil
yaitu 4-6%.(15)
 DAFTAR PUSTAKA
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Nivedithaa & Saba Maanvizhi RJLBPCS 2018 www.rjlbpcs.com Life Science Informatics Publications

Original Research Article DOI - 10.26479/2018.0401.15

FORMULATION AND EVALUATION OF IMMEDIATE RELEASE
COMBINATION TABLET FOR CARDIOVASCULAR DISEASES
Nivedithaa V.R.1*, Saba Maanvizhi 2
1. Department of Pharmaceutics, Sri Ramachandra Medical College and Research Institute,
Chennai, India
2.Department of Pharmaceutics, Sri Ramachandra Medical College and Research Institute,
Chennai, India.

ABSTRACT: Obesity is known to have significant impact on physical and psychological health
related issues in many countries. Although researcher has shown good results achieved by combine
dietary, exercise and behavioral therapy interventions, but it needs multi-drug at different levels of
treatment lead to patient non-compliance. Therefore, combination therapy of Atorvastatin Calcium,
a lipid lowering agent and Bisoprolol Fumarate, an antihypertensive agent was preferred for obesity
treatment. The present research work was envisaged to develop immediate release tablet of
Atorvastatin Calcium and Bisoprolol Fumarate by direct compression method to minimize dose-
dependent side effect and improve patient compliance for obese people. The physical parameters
were carried out as per standard USP procedures. In vitro dissolution studies were carried out in USP
dissolution apparatus type II, using pH 1.2 HCl buffer. The formulation that showed more than 90%
release was considered to be optimized formulation of combination tablet. Study reveals that
combination of beta-blocker and statins were good candidate for blood pressure and lowering
lipoproteins in obese patient and may increases patient compliance by reducing the multi dosage form
therapy and prescription costs.
KEYWORDS: Combination tablet, Atorvastatin Calcium, Bisoprolol Fumarate, hypertensive, dyslipidemia.

*Corresponding Author: Nivedithaa V.R.

Department of Pharmaceutics, Sri Ramachandra Medical College and Research Institute, Chennai,
India
* Email Address: niviraj95@gmail.com

INTRODUCTION
There is a constant risk of obesity in various countries, which leads to many other risk factors related
to heart and other major organs, due to fat deposit. Various problems related to Obesity are
Hyperlipoproteinemia, Hypercholesterolemia, Atherosclerosis, Hypertension, Diabetes,
Cardiovascular diseases etc. These disorders or diseases require multidrug treatments at various time
periods, which can lead to patient non-compliance[1]. To improve patient compliance and improve
bioavailability of drugs, combination of two or more drugs in the form of tablets or capsules were
formulated. The combination of a beta-blocker and cholesterol lowering agent drugs with acceptable
adjuvants is a better method of treatment of obesity[1][2]. Atorvastatin Calcium, a lipid lowering
© 2018 Life Science Informatics Publication All rights reserved
Peer review under responsibility of Life Science Informatics Publications
2018 Jan-Feb RJLBPCS 4(1) Page No.176
Nivedithaa & Saba Maanvizhi RJLBPCS 2018 www.rjlbpcs.com Life Science Informatics Publications
agent, is a HMGCoA inhibitor which is a rate limiting step in cholesterol synthesis and it belongs to
Class II compound of BCS Classification. Bisoprolol Fumarate is known to have a positive effect on
various cardiovascular diseases, especially hypertension. Bisoprolol Fumarate is also said to suppress
atrial fibrillation. Bisoprolol Fumarate belongs to Class I of the BCS Classification. According to
literatures, extensive works have been done on individual drugs, but not as a combination of these
two drugs using different superdisintegrants, as immediate release formulations[3][4]. Hence,
Atorvastatin Calcium and Bisoprolol Fumarate, were considered for formulation of immediate release
tablet, in order to reduce total dose of drug needed in a day and also dosing frequency. In this study,
various formulations for the combination therapy of Bisoprolol Fumarate and Atorvastatin Calcium
were carried out with varying superdisintegrant concentrations and all the formulations were subjected
to drug release studies and further fitted to various kinetic models[5]. Finally formulation was
optimized based on drug release studies.
TABLE I - PHYSICOCHEMICAL PARAMETERS OF ATORVASTATIN CALCIUM AND BISOPROLOL
FUMARATE

Physicochemical
Atorvastatin Calcium Bisoprolol Fumarate
Parameters
Competitive, cardioselective β1-
Selective, competitive HMG-CoA
Pharmacodynamics adrenergic antagonist. Lower the
reductase inhibitor.
heart rate and blood pressure.
HMG-CoA reductase is in control of Selectively blocks stimulation of
converting HMG-CoA to mevalonate in β1-adrenergic receptors in heart
Mechanism of the cholesterol biosynthesis pathway, and vascular muscle, which
action Atorvastatin Calcium, inhibits the reduces heart rate, cardiac output,
hepatic enzyme, which reduces hepatic blood pressure and reflex
cholesterol levels. hypotension.
Rapid absorption after oral Well absorbed, bioavailability
Absorption administration with maximum plasma more than 80%. absorption not
concentrations achieved in 1 to 2 hours. affected by food.
Half life 14 hours 9-12 hours
Volume of
381 Litres 3.51 Litres/Kg
Distribution
Approximately 30% bound to
Protein Binding >98% bound to plasma proteins
serum proteins.
CYP3A4 engages in the metabolism of 50% primarily metabolized by
Metabolism
Atorvastatin calcium CYP3A4 to inactive metabolites.
50% dose administered,
Route of After hepatic metabolism eliminated in eliminated unchanged in urine,
Elimination bile. with remainder appearing as
inactive metabolites.
MATERIALS AND METHODS
Atorvastatin Calcium and Bisoprolol Fumarate were received as a gift sample from Amoli Organics
Pvt. Ltd., Vadodara and Mangalam Drugs, Mumbai respectively. Other chemicals used were of
analytical grade.
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Precompression studies:
Precompression studies were performed, to check drug-drug and drug-excipient interactions. Drugs
proposed to be used, both alone and in combination along with excipients to be used, was filled into
amber colored vials and sealed with rubber stoppers and placed in stability chamber (Remi Lab,
Mumbai, India) for accelerated condition at 40 ± 2oC and 75 ± 5 % RH for 30 days. IR spectra of the
samples were obtained with FT-IR spectrophotometer (FTIR-8001, Shimadzu, Japan) and compared
with the initial spectra of drugs.
Development of Atorvastatin Calcium and Bisoprolol Fumarate of Immediate Release
Combination tablet:
Various composition of formulation trials are given in Table II. The corresponding amount of drugs
were weighed and screened through 40 mesh sieve (425µ) belonging to ASTM (American Standard
Test Sieves)[6][7]. Similarly, Microcrystalline Cellulose, Lactose and other ingredients were also
weighed and passed through 40 mesh sieve. The sifted powders were transferred into a polybag and
sealed properly. The contents of the polybag were mixed thoroughly for 5 minutes. After each round
of mixing the contents of the bag were passed through screen no.40. The blend was again mixed
thoroughly in the polybag[8]. The blend was subjected to physical evaluation. The blend was
compressed into tablets using 8-station rotary tablet compression machine (Kambert, 8 station,
Ahmadabad) equipped with punches of beveled flat-face, 8mm diameter, a tablet weight of 230mg.
The tablets were collected after compression for in-process testing (weight, hardness, and
friability).[9]
TABLE II - FORMULATION TRIALS OF ATORVASTATIN CALCIUM AND BISOPROLOL
FUMARATE COMBINATION TABLET
Quantity per tablet (mg)
Ingredients
F1 F2 F3 F4 F5
Atorvastatin Calcium 10 10 10 10 10
Bisoprolol Fumarate 2.5 2.5 2.5 2.5 2.5
Microcrystalline cellulose 100.5 100 100 100 100
Lactose 111 110.5 110.5 109.5 107.5
Magnesium stearate 2 2 2 2 2
SLS 2 2 3 3 4
Sodium starch glycolate 2 3 2 3 4
Tablet fill weight 230mg

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Figure I - Atorvastatin Calcium and Bisoprolol Fumarate IR Tablets

Evaluation of Blend:
Lubricated blend of Atorvastatin Calcium and Bisoprolol Fumarate IR tablets, prior to compression,
was characterized for physical parameters like angle of repose, bulk density and tapped density and
percentage compressibility.[10]
Evaluation of Tablets:
Compressed tablets properties, like, Thickness (Digital Vernier Caliper, Mitutoyo Corp., New Delhi),
Hardness (Pfizer hardness tester, Pfizer, Haryana), Friability (Inlab equipments Pvt. ltd., Madras),
Disintegration time (Inlab equipments Pvt. ltd., Madras) and Weight Variation was evaluated. The
content of Atorvastatin Calcium and Bisoprolol Fumarate in IR tablets was determined as per the
procedure in USP.[11]
Calibration Curve for Atorvastatin Calcium:
Preparation of Stock Solution :- 50mg of Atorvastatin Calcium was weighed and dissolved in 50ml
of Methanol in a 50ml volumetric flask. (Concentration 1mg/ml)
10ml of stock solution was diluted to 100ml with Methanol to get a concentration of 10µg/ml, and
scanned in the range of 200 - 400nm and the λmax was found to be 241nm.[12]
From standard stock solution,2.5ml was withdrawn and diluted to 25ml with methanol in a 25ml
volumetric flask. From the above solution, 0.5ml, 1ml, 1.5ml, 2ml, and 2.5ml was withdrawn and
added to 10ml volumetric flask and volume made up with Methanol to obtain concentration in the
range of 5-25µg/ml. The absorbance was recorded at 241nm.
Calibration Curve for Bisoprolol Fumarate:
Preparation of Stock Solution :- 5mg of Bisoprolol Fumarate was weighed and transferred to a 100ml
volumetric flask, and dissolved using about 50ml of distilled water and the volume made up to 100ml
with distilled water. (Concentration 50µg/ml)

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The above stock solution itself was used to estimate the λmax of Bisoprolol fumarate scanning from a
range of 200 to 400nm and it was found to be 222nm.[13]
From Standard stock solution, 1,2,3,4 and 5ml solution was pipetted out into 10ml volumetric flasks
and the volume made up with distilled water, to obtain final concentration of 5,10,15,20 and 25µg/ml.
The absorbance was recorded at 222nm.
In vitro drug release:
In vitro dissolution studies was carried out as per USP specifications. The USP dissolution test
apparatus type II (Electrolab, TDT 08L, USP) at 75 rpm was used for studies[14]. 900ml of 0.1N HCl
was used as the dissolution medium at 75rpm maintained at a temperature of 37.5°c ± 0.5°c. Aliquots
of sample were withdrawn at specific time intervals, filtered and replaced with buffer to maintain sink
condition[15]. The absorbance of the filtered solution were measured at 222nm and 241nm for
Bisoprolol fumarate and Atorvastatin calcium respectively for drug content determination.
Assay of Bulk drug:
20mg of Atorvastatin Calcium and 5mg of Bisoprolol Fumarate were accurately weighed and
transferred into a 100ml volumetric flask, and dissolved in 50ml of methanol and the volume was
made up with the same. Appropriate dilutions were made using methanol to obtain concentrations of
20µg/ml of Atorvastatin Calcium and 10µg/ml of Bisoprolol Fumarate[16][17]. The resulting
solutions were analyzed at wavelengths 241nm and 222nm respectively.
Assay of Formulated Tablet (Simultaneous Equation Method):
Twenty tablets having label claim of 10mg of Atorvastatin Calcium and 2.5mg of Bisoprolol Fumarate
were weighed, their average taken and crushed into fine powder. The powder equivalent to 10mg of
Atorvastatin Calcium and 2.5mg of Bisoprolol Fumarate was weighed accurately and transferred into
100ml volumetric flask and about 50ml of methanol was added and the flask was sonicated for 15-20
minutes. The solution was filtered through whatman grade filter paper and the volume was made up
to 100ml with methanol. From this solution, appropriate dilution was made to obtain concentration of
20µg/ml of Atorvastatin Calcium and 10µg/ml of Bisoprolol Fumarate[18]. The resulting solution was
analyzed at the wavelengths 241nm and 222nm.
Drug Release Kinetics Model:
Mathematical models of release kinetics studies plays a important role as it provides mechanism of
drug release and more general guidelines for the development of various systems. Such models can
be used for optimization of release kinetics, to deduct mass transport mechanisms, to design new drug
delivery systems based on general release expressions[19].
The mathematical models was used to evaluate the mechanism of drug release from the tablets and
kinetics. Based on the correlation coefficient (r) value in various models, the model that best fits the
release data was selected. The model giving the high 'r' value was considered as the best fit of the
release data. Goodness of fit test is the criterion for selecting the best fit model
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The mathematical models used were:[20]
i. Zero Order Kinetics Model
ii. First Order Kinetics Model
iii. Higuchi Model
iv. Korsmeyer-Peppas Model
RESULTS AND DISCUSSIONS
Precompression Studies:
The FT-IR spectra were compared of physical mixture of drugs after 30 days of accelerated stability
(Figures II, III and IV). The physical appearance of the samples was not changed and the spectras
showed no additional peaks when compared to their individual IR spectrum. The physical mixture of
drug with the excipients used also showed no interactions between them in the spectras.

Figure II - FTIR spectra of Atorvastatin Calcium pure drug

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Figure III - FTIR Spectra of Bisoprolol Fumarate Pure drug

Figure IV - FTIR Spectra of Combination of Atorvastatin Calcium and Bisoprolol Fumarate

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Blend Evaluation:
The powder blend thus prepared was evaluated and the results thus obtained were given in Table III.
TABLE III - BLEND CHARACTERIZATION OF ATORVASTATIN CALCIUM AND BISOPROLOL
FUMARATE IR BLEND
Bulk Tapped Carr's
Angle of Hausner's
FORMULATIONS Density Density Index
Repose (°) ratio
(gm/ml) (gm/ml) (%)
F1 31.25 0.40 0.45 12.5 1.12
F2 29.50 0.40 0.45 12.5 1.12
F3 28.95 0.43 0.50 15.9 1.16
F4 28.30 0.38 0.42 10.52 1.10
F5 30.45 0.41 0.47 14.63 1.14

Angle of repose for the powder blends of all the formulations were within the limits, to indicate good
flow property. The bulk density of the powder blend of all formulations along with drugs and the
excipients was found to be in the range of 0.38gm/ml to 0.43gm/ml, whereas tapped density was found
to be in the range of 0.42gm/ml to 0.50gm/ml. From bulk density and tapped density values of Carr's
index and Hausner's ratio was calculated. The value of Carr's index was found to be between 10.52 to
15.9. The value of Hausner's ratio was found to be between 1.10 to 1.16. All the above obtained values
were within the specified limits which indicates good flow property and compressibility of the blend.
Overall the blend showed good flow property which indicated better hopper flow and die fill and
better compressibility.
Physical Evaluation of Tablets:
Table IV shows the results for the Physical evaluation parameters of the formulated tablets.
TABLE IV - EVALUATION OF ATORVASTATIN CALCIUM AND BISOPROLOL FUMARATE
COMBINATION TABLETS
FORMULATIONS
PARAMETERS
F1 F2 F3 F4 F5
Weight(mg) 228.55 230.85 230.5 228.65 229.8
Diameter(mm) 8 8 8 8 8
Thickness(mm) 4 4 4 4 4
Hardness(N) 6 7 6 6 8
Friability(%) 0.25 0.27 0.24 0.26 0.24
Disintegration 7 6.5 6 5 5
Time(min)

The weight variation of all the tablets were within the limits as specified in I.P (the limit should not
exceed ±7.5), that implies that there is uniformity in powder flow. The thickness of all the formulations
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was found to be uniform indicating good flow to the die during compression. Hardness for all the
formulations was proper, which proves good tensile strength. Test for friability lies within the range
of I.P. specifications, i.e. less than 1% indicating the formulations to have good physical strength.
Disintegration time was found to be in the range of 5 to 7 minutes depending upon the concentration
of the disintegrant added, and also was within the range of I.P. specifications for any conventional
release tablets. Disintegration time of formulation F4 was found to be 5 minutes, which is more
suitable for immediate release tablets as per specifications.
Calibration:
The absorbance for the calibration of Atorvastatin Calcium and Bisoprolol Fumarate are given in
tables V and VI respectively. Their respective calibration curves are given in figures V and VI. The
linearity range of Atorvastatin Calcium is 5-25µg/ml and the linearity range of Bisoprolol Fumarate
is 5-25µg/ml.
Calibration Curve of Atorvastatin Calcium:
TABLE V: CALIBRATION CURVE OF PURE DRUG ATORVASTATIN CALCIUM
Concentration
S.No Absorbance
(µg/ml)
1 5 0.2389
2 10 0.4857
3 15 0.7108
4 20 0.9553
5 25 1.2204

Calibration Curve of Bisoprolol Fumarate:

TABLE VI: CALIBRATION CURVE OF PURE DRUG BISOPROLOL FUMARATE

Concentration
S.No Absorbance
(µg/ml)
1 5 0.2471
2 10 0.4561
3 15 0.7011
4 20 0.9751
5 25 1.2234

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Calibration Curve of Atorvastatin Calcium

1.4
y = 0.0484x - 0.0036
1.2
R² = 0.9996
1
Absorbance

0.8

0.6

0.4

0.2

0
0 5 10 15 20 25 30
Concentration (µg/ml)

Figure V: Calibration Curve of Atorvastatin Calcium

Calibration Curve of Bisoprolol Fumarate

1.4
y = 0.0488x - 0.01
1.2
R² = 0.9986
1

0.8
Absorbance

0.6

0.4

0.2

0
0 5 10 15 20 25 30
-0.2
Concentration (µg/ml)

Figure VI: Calibration Curve of Bisoprolol Fumarate

In Vitro Drug Release:

In vitro drug release study was conducted over a period of 60 minutes., all the formulations showed
gradual increase in drug release. Table VII and VIII shows the Percent Drug release for Atorvastatin
Calcium and Bisoprolol Fumarate respectively. Formulations F3 and F4 showed better drug release
for both Atorvastatin Calcium and Bisoprolol Fumarate. Hence Formulations F3 and F4 showed quick

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and better release as it contains highest percentage of disintegrant concentration. Figures VII and VIII
show the graphical representation of percent drug released. Formulations F3 and F4 showed a drug
release of 93.2% and 96.29% for Atorvastatin Calcium respectively and 91.25% and 92.01% for
Bisoprolol Fumarate respectively and hence optimized as immediate release tablets.
TABLE VII - DISSOLUTION PROFILE OF ATORVASTATIN CALCIUM
PERCENT DRUG RELEASED (%) (Atorvastatin Calcium)
TIME (min)
F1 F2 F3 F4 F5
10 39.25 35.47 32.09 30.27 34.29
20 46.47 49.28 48.91 49.21 48.79
30 69.95 70.51 65.14 67.29 67.28
45 85.97 84.01 82.53 85.20 80.21
60 89.32 88.79 93.20 96.29 89.81

TABLE VIII- DISSOLUTION PROFILE OF BISOPROLOL FUMARATE

PERCENT DRUG RELEASED (%) (Bisoprolol Fumarate)
TIME (min)
F1 F2 F3 F4 F5
10 41.05 37.09 40.57 41.34 39.81
20 67.39 63.27 61.97 60.20 62.61
30 75.81 73.20 75.29 72.61 75.28
45 80.63 81.94 83.67 84.57 83.63
60 85.17 87.84 91.25 92.01 88.83

Atorvastatin Calcium
120
Percentage Drug Release (%)

100

80
F1
60 F2
F3
40
F4
20 F5

0
0 10 20 30 40 50 60 70
Time (min)

Figure VII - Percentage Drug Release of Atorvastatin Calcium in F1-F5

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Bisoprolol Fumarate
100
Percentage Drug Release (%) 90
80
70
60 F1
50 F2
40 F3
30 F4
20
F5
10
0
0 10 20 30 40 50 60 70
Time (min)

Figure VIII - Percentage Drug Release of Bisoprolol Fumarate in F1-F5

Assay of Bulk Drug and Formulated Tablet:
The assay of the formulated tablets was performed by Simultaneous equation method. The assay of
Bulk Drug (20mg Atorvastatin Calcium and 5mg of Bisoprolol Fumarate) and that of Formulated
tablets (10mg Atorvastatin Calcium and 2.5mg of Bisoprolol Fumarate) was analyzed using UV
Spectroscopic method at the respective wavelengths.
The percent drug content in the Bulk drug was found to be 100.84% and 101.03% for Atorvastatin
Calcium and Bisoprolol Fumarate respectively. The drug content of Formulated tablet was found to
be 98.1% and 99.7% for Atorvastatin Calcium and Bisoprolol Fumarate respectively.
Drug Release Kinetics:
The drug profiles from the combination tablets were fitted into various mathematical kinetic models..
The values of correlation coefficient (r2) and release rate constants (K) from different models for the
prepared tablets are given in Tables IX and X for Atorvastatin Calcium and Bisoprolol Fumarate
respectively. From the data of correlation coefficient and rate constant values, the drug release from
all the formulations, was found to obey the first order release followed by the Korsmeyer Peppas
kinetic model.

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TABLE IX- CORRELATION COEFFICIENT (r2) & RATE CONSTANT (K) VALUES OF
ATORVASTATIN CALCIUM
KINETIC
F1 F2 F3 F4 F5
MODEL
ZERO K 1.0928 1.0997 1.2262 1.3193 1.1156
ORDER r2 0.9181 0.9208 0.9726 0.9663 0.9575
FIRST K 0.0167 0.0149 0.0089 0.0096 0.0163
ORDER r2 0.9633 0.9347 0.9102 0.892 0.9942
K 12.208 12.393 13.668 14.741 12.48
HIGUCHI
r2 0.9446 0.9642 0.9962 0.9946 0.9878
K 1.0463 0.5441 0.6081 0.6588 0.5543
PEPPAS
r2 0.8949 0.9745 0.9965 0.9933 0.9897

TABLE X - CORRELATION COEFFICIENT (r2) & RATE CONSTANT (K) VALUES OF BISOPROLOL
FUMARATE
KINETIC
F1 F2 F3 F4 F5
MODEL
ZERO K 0.7718 0.9239 0.9514 0.9797 0.9156
ORDER r2 0.7704 0.8497 0.8963 0.9355 0.8632
FIRST K 0.0111 0.0137 0.0162 0.0127 0.0144
ORDER r2 0.9107 0.9762 0.9938 0.999 0.9802
K 8.9934 10.623 10.863 11.059 10.503
HIGUCHI
r2 0.8623 0.924 0.9598 0.9827 0.9366
K 0.3945 0.4715 0.45 0.4496 0.391
PEPPAS
r2 0.8914 0.9318 0.9673 0.9879 0.8398

CONCLUSION
The combination tablet of Atorvastatin Calcium and Bisoprolol Fumarate was formulated
successfully by direct compression method. Direct compression method is more feasible and less time
consuming. Combination tablets were formulated to increase patient compliance and prevent intake
of multiple drug therapy. Precompression parameter confirmed that, there was no interaction observed
between drug-drug and drugs with various excipients which was used in the development of the
formulations. The values of angle of repose indicated satisfactory flow behavior. The prepared
formulation were within the specifications as per USP for the post compression parameter. Maximum
drug release was observed for formulation F3 and F4 in 60 minutes. Both formulations F3 and F4 can
be considered for further studies and development of the formulation. The release exponent (n) was
calculated to be close to 1 in both first order and korsmeyer peppas release kinetics. The mechanism
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for drug release was found to be through first order release followed by Korsmeyer peppas drug
release kinetic model (Table 9 and 10). Thus from the results obtained, it can be concluded that the
immediate release tablets of 230 mg of Atorvastatin Calcium and Bisoprolol Fumarate has
successfully developed. Further long term stability studies are required to establish stable tablet
formulation and to establish its efficacy in the treatment of hyperlipoproteinemia and hypertension.
The study resulted in developing a Atorvastatin Calcium and Bisoprolol Fumarate commercially by
reducing formulation cost. Hence such tablets can be exploited for use in obesity treatment.
CONFLICT OF INTEREST
There are no conflicts of interest to disclose.
ACKNOWLEMENT
The author would like to thank Sri Ramachandra University for providing the opportunity and the
facility to carry out the research work. The author would also like to thank Amoli Organics Pvt. Ltd,
Vadodra and Mangalam Drugs, Mumbai for providing the raw materials required for the study.
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