Sediaan Farmasi: "SIROP"

SIROP

(Sirupi)

Oleh:

OKTAFIAN V.F. Kawulusan

A.   Sejarah & Pengertian Sirop

Sirop telah dikenal sebagai bentuk sediaan obat sejak masa Arab kuno yang dikenalkan

oleh Avicenna (Ali Ibnu Sina), ahli farmasi berkembangsaan Arab. Istilah “Sirop” diduga berasal

dari kara “Sirab” (Bah. Arab), yang artinya adalah sari pati gula. Berikut ini, beberapa definisi

tentang sirop:

   Sirop adalah sediaan pekat dalam air dari gula atau pengganti gula dengan atau tanpa

penambahan bahan pewangi dan zat obat (Ansel, 1989).

  Sirop adalah sediaan cairan kental mengandung sukrose (gula) tidak kurang dari 50% dan tidak

lebih dari 65%, dapat mengandung satu atau lebih bahan obat (Priyambodo, 2007).

   Sirop adalah bentuk sediaan cair yang mengandungSaccharosa atau gula. Konsistensi sirup

kental karena kadar Saccharosa yang tinggi, yaitu 64,0-66,0% (Zaman-Joenoes, 2008).

  Sirop adalah sediaan cair berupa larutan yang mengandung sakarosa. Kecuali dinyatakan lain,

kadar sakarosa, C12H22O11, tidak kurang dari 64.0% dan tidak lebih dari 66,0%.

B.   Penggolongan Sirop

Bedasarkan fungsinya, sirop dikelompokan menjadi 2 golongan, yaitu:

1.    Medicated Syrup (sirop obat) merupakan sirup yang mengandung satu atau lebih bahan obat.

Sirop obat berupa preparat yang sudah distandarisasi, dapat diberikan berupa obat tunggal

atau dikombinasikan dengan obat lain. Contoh sirop obat antara lain:

a.    Sirop sebagai ekspektorans:

  Sirop Thymi.

  Sirop Thymi et Serpylli = Sirop Thymi Compositus.

  Sirop Althae.

b.    Sirop sebagai antitusif:

  Sirop Codeini, mengandung 2 mg Codein/ml sirop.

c.    Sirop sebagai anthelmintik:

   Sirop Piperazini, mengandung 1 g Piperazine dalam bentuk hexahydrat/citrat dalam tiap 5 ml

sirop.

d.    Sirop sebagai antibiotik

  Sirop Kanamycin, mengandung 50 mg/ml.

  Sirop Chloramphenicol, umumnya mengandung 25 mg/ml.

  Sirop Ampicillin, umumnya mengandung 25 mg/ml.

  Sirop Amoxycillin, umumnya mengandung 25 mg/ml.

  Sirop Cloxacillin, umumnya mengandung 25 mg/ml.

e.    “Dry Syrup” atau sirop kering, berupa campuran obat dengan sakarosa, harus dilarutkan dalam

jumlah air tertentu sebelum dipergunakan. Keuntungan sirop kering dari pada sirop cairan,

biasanya sirop kering dapat tahan disimpan lebih lama. Contohnya Ampicillin trihydrate “dry

syrup”, ekivalen dengan 25 mg/ml sirop cairan kalau sudah dilarutkan dalam jumlah air yang

ditentukan.

2.    Flavored Syrup (sirop korigen/pembawa), biasanya tidak digunakan untuk tujuan medis, namun

mengandung berbagai bahan aromatis atau rasa yang enak dan digunakan sebagai larutan

pembawa atau pemberi rasa pada berbagai sediaan farmasi lainnya, misalnya sebagai penutup

rasa pahit pada Vitamin B Kompleks yang diberikan kepada bayi atau anak-anak. Sirop

golongan ini, mengandung berbagai bahan tambahan, misalnya bahan antioksidan (antioxidant

agent), pengawet (preservative agent), pewarna (coloring agent), pemberi rasa (flavoring

agent), dan bahan pelarut (diluting agent). Sirop ini, ditambahkan sebagai korigens rasa untuk

obat minum, cukup dalam jumlah 10-20 ml untuk tiap 100 ml larutan obat. Sirop yang sering

dipakai sebagai korigens-rasa, yaitu:

a.    Sirop Simpleks, mengandung 65% gula dalam larutan nipagin 0,25% b/v.

b.    Sirop Aurantii, terutama untuk bahan obat yang rasanya pahit.

c.    Sirop Rubi Idaei, terutama untuk bahan obat yang rasanya asam.

C.   Formula & Pembuatan Sirop

Sebagian besar sirop mengandung komponen-komponen berikut disamping air murni

(purified water) dan semua zat-zat obat yang ada:

   Gula, biasanya sukrosa atau pengganti gula yang digunakan untuk memberi rasa manis dan

kental.

  Pengawet antimikroba.

  Pembau.

  Pewarna.

Juga banyak sirop, terutama yang dibuat dalam perdagangan, mengandung pelarut-pelarut

khusus, pembantu kelarutan, pengental dan stabilisator.

Menurut Farmakope Indonesia edisi III (1979), kecuali dinyatakan lain, sirop dibuat

sebagai berikut:

  Buat cairan untuk sirop, panaskan, tambahkan gula, jika perlu didihkan hingga larut. Tambahkan

air mendidih secukupnya hingga diperoleh bobot yang dikehendaki, buang busa yang terjadi,

serkai.

   Pada pembuatan sirop dari simplisia yang mengandung glukosida antrakuinon, ditambahkan

natrium karbonat sejumlah 10% bobot simplisia.

   Kecuali dinyatakan lain, pada pembuatan sirop simplisia untuk persediaan ditambahkan metil

paraben 0,25% b/v atau pengawet lain yang cocok.

Dalam produksi besar di industri farmasi, pemilihan bahan yang digunakan untuk

pembuatan sediaan sirop harus dilakukan dengan hati-hati, termasuk air yang digunakan juga

harus memenuhi persyaratan air untuk produk farmasi (purified water). Kebersihan wadah dan

alat untuk produksi juga memegang peranan yang sangat penting. Hal lain yang mempengaruhi

proses pembuatan sirop adalah karakteristik bahan baku yang digunakan, peralatan, prosedur

pencampuran dan pengisian ke dalam wadah.

Bahan baku yang digunakan dalam proses pembuatan sediaan sirop harus sesuai

dengan spesifikasi yang telah ditentukan dan ditentukan secara cermat. Spesifikasi tersebut

harus bisa menjamin ciri-ciri, kemurnian, homogenitas, dan bebas dari kontaminasi mikroba

yang berlebihan. Selain bahan aktif, air juga merupakan faktor yang sangat kritis dalam proses

pembuatan sediaan sirop, karena merupakan komponen terbesar.

Peralatan yang digunakan untuk proses pembuatan sediaan sirop terdiri dari tangki

pencampur yang dilengkapi dengan pengaduk berkecepatan tinggi, penyaring, dan pengisi

sirop ke dalam wadah (botol). Tangki, umumnya dibuat dari bahan baja anti-karat AISI 316 yang

dipoles berlapis dua (double jacket), dimana panas dari uap air (steam boiler) yang digunakan

untuk memanaskan sirop dilewatkan diantara kedua dinding tangki. Tangki tersebut bisa ditutup

dengan rapat sehingga lebih efektif.

Proses pembuatan sediaan sirop dapat dilakukan dengan beberapa metode/cara,

tergantung dari bahan yang digunakan, terutama menyangkut sifat-sifat fisik dan kimia dari

bahan aktif. Metode pembuatan sirop tersebut antara lain:

  Metode pelarutan dengan pemanasan.

  Metode pengadukan tanpa pemanasan.

   Metode penambahan bahan aktif ke dalam sirup sederhana (Sirop Simpleks atau Flavoring

Syrup).

  Metode perkolasi.

Metode pembuatan sediaan sirop dengan menggunakan pemanasan merupakan

metode yang paling umum digunakan, sangat cocok digunakan untuk bahan-bahan yang tidak

rusak akibat pemanasan serta apabila dikehendaki proses pembuatan sirop secara cepat.

Mula-mula gula (sucrose) dilarutkan di dalam air murni (purified water) yang telah

dipanaskan pada suhu 50-700C sambil diaduk hingga larut. Selanjutnya bahan aktif dan bahan

pengawet dimasukkan ke dalam larutan gula dan diaduk hingga semua bahan larut sempurna,

kemudian didinginkan hingga suhu 300C. Masukkan ke dalam larutan tersebut bahan-bahan

tambahan lain (pengental, pewarna dan perasa), aduk hingga homogen. Saring larutan dengan

penyaring yang sesuai, selanjutnya sirop tersebut dimasukkan ke dalam wadah. (botol) yang

dikehendaki dan dilakukan proses pengemasan. Hal yang sangat penting dalam proses

pembuatan sediaan sirop dengan metode ini adalah suhu jangan sampai terlalu tinggi (>700C)

karena akan menyebabkan terjadinya inversin gula menjadi gula inert serta karamelisasi gula

yang di tandai dengan warna sirop menjadi cokelat.

Untuk bahan-bahan yang tidak tahan (rusak) atau menguap apabila dipanaskan, maka

dapat digunakan metode pengadukan tanpa pemanasan, penambahan bahan aktif ke dalam

sirup sederhana atau metode perkolasi.

Pada sirop dengan kadar gula rendah dapat terjadi fermentasi, kadar gula yang tinggi

mempunyai tekanan osmotik yang cukup tinggi sehingga pertumbuhan bakteri dan fungi dapat

terhambat. Bila sebagian dari sakarosa berubah menjadi gula invert, maka sirop cepat menjadi

rusak. Kerusakan sirop dapat dihindarkan dengan menambahkan suatu bahan pengawet ke

dalam sirop, misalnya Nipasol, Nipagin atau Natrium Benzoat.

Selain sukrosa dan gula lain, pada sirop dapat ditambahkan senyawa poliol seperti

sorbitol dan gliserin untuk menghambat penghabluran dan mengubah kelarutan, rasa dan sifat

lain zat pembawa. Umunya juga dalam pembuatan sirop, ditambahkan zat antimikroba untuk

mencegah pertumbuhan bakteri dan fungi.

Penetapan kadar sakarosa dalam sirop menurut Farmakope Indonesia edisi III (1979)

adalah sebagai berikut:

Timbang saksama lebih kurang 25 g sirop dalam labu tentukur 100 ml, tambahkan 50 ml

air dan sedikit larutan aluminium hidroksida P. Tambahkan larutan timbal (III) subasetat P tetes

demi tetes hingga tetes terakhir tidak menimbulkan kekeruhan.

Tambahkan air secukupnya hingga 100 ml, saring, buang 10 ml filtrat pertama.

Masukkan 50,0 ml filtrat ke dalam labu tentukur 55 ml, tambahkan campuran 79 bagian volume

asam klorida P dan 21 bagian volume air secukupnya hingga 55,0 ml. Panaskan labu dalam

tangas air pada suhu antara 680 C dan 700 C selama 10 menit, dinginkan dengan cepat

sehingga suhu lebih kurang 200 C. Jika perlu hilangkan warna menggunakan tidak lebih dari

100 mg arang jerap P. Ukur rotasi optik larutan yang belum diinversi menggunakan tabung 22,0

cm pada suhu pengukur yang sama antara 100 C dan 250 C. Hitung kadar dalam % C12H22O11,

dengan rumus:

300xα1-α2

C= ------------------------

(144-0,5t)

Keterangan:

α1 adalah rotasi optik larutan yang belum diinversi.

α2 adalah rotasi optik larutan yang telah diinversi.

T adalah suhu.

Penyimpanan sirop menurut anjuran Farmakope Indonesia edisi III (1979), dalam wadah

tertutup rapat, di tempat sejuk.

Pustaka:

Ansel HC, 1989.Pengantar Bentuk Sediaan Farmasi. Penerjemah Farida Ibrahim; Pendamping Asmanizar, Iis Aisyah. Jakarta: Penerbit Universitas Indonesia (UI Press).

Priyambodo B, 2007. Manajemen Farmasi Industri. Yogyakarta: Global Pustaka Utama.

Syamsuni HA, 2006. Ilmu Resep. Jakarta: EGC.

Tim Penyusun Farmakope Indonesia, 1979. Farmakope Indonesia Edisi III. Jakarta: Departemen Kesehatan Republik Indonesia.

Zaman-Joenoes N, 2008. Ars Prescribendi Resep yang Rasional. Surabaya: Airlangga University Press.

Tekhnologi Farmasi (Sediaan Sirup)

Sirup adalah salah satu bentuk sediaan cair yang dalam dunia farmasi yang dikenal luas oleh masyarakat. Saat ini, banyak sediaan sirup yang beredar di pasaran dari berbagai macam merk, baik yang generic maupun yang paten. Biasanya, orang-orang mengunakan sediaan sirup karena disamping mudah penggunaannya, sirup juga mempunyai rasa yang manis dan aroma yang harum serta warna yang menarik sehingga disukai oleh berbagai kalangan, terutama anak-anak dan orang yang susah menelan obat dalam bentuk sediaan oral lainnya.

Sirup didefinisikan sebagai sediaan cair yang mengandung sakarosa. Kecuali dinyatakan

lain, kadar sakarosa tidak kurang dari 64% dan tidak lebiih dari 66%. Secara umum, sirup dibagi

menjadi 2 macam yaitu Non Medicated Syrup/Flavored Vehicle Syrup (Seperti cherry syrup,

cocoa syrup, orange syrup) dan Medicated Syrup/Sirup Obat (Seperti sirup piperazina sitrat,

sirup isoniazid). Non Medicated Sirup adalah sediaan syrup yang tidak mengandung bahan obat,

melainkan hanya mengandung gula, perasa, pengawet dan perwarna sedangkan Sirup Obat

mengandung bahan obat/Zat berkhasiat.

Definisi

Menurut farmakope Indonesia III, sirup adalah sedian cair berupa larutan yang mengandung

sakarosa, C12H22O11, tidak kurang dari 64.0% dan tidak lebih dari 66.0%.

Sirup adalah larutan oral yang mengandung sukrosa atau gula lain dalam kadar tinggi

(Anonim, 1995). Secara umum sirup merupakan larutan pekat dari gula yang ditambah obat atau

zat pewangi dan merupakan larutan jernih berasa manis. Syrup adalah sediaan cair kental yang

minimal mengandung 50% sakarosa (Ansel et al., 2005).

Dalam perkembangannya, banyak sekali pengertian mengenai sirup. Sirup adalah sediaan

cair berupa larutan yang mengandung sakarosa (Anonim, 1979). Sirup adalah sediaan cairan

kental untuk pemakaian dalam, yang minimal mengandung 90% sakarosa (Voigt, 1984).

Penggolongan Sirup

Bedasarkan fungsinya, sirup dikelompokan menjadi 2 golongan, yaitu:

1.      Medicated Syrup (sirup obat)

Merupakan sirup yang mengandung satu atau lebih bahan obat. Sirup obat berupa preparat

yang sudah distandarisasi, dapat diberikan berupa obat tunggal atau dikombinasikan dengan obat

lain. Contoh sirup obat antara lain: Sirup sebagai ekspektorans contohnya yaitu Sirup Thymi.

Sirup Thymi et Serpylli = Sirop Thymi Compositus. Sirop Althae. Sirup sebagai antitusif, contoh

sirup Codeini, mengandung 2 mg Codein/ml sirop.

Sirup sebagai anthelmintik: cotoh sirup Piperazini, mengandung 1 g Piperazine dalam bentuk

hexahydrat/citrat dalam tiap 5 ml sirop. Sirup sebagai antibiotik contohnya yaitu Sirup

Kanamycin, mengandung 50 mg/ml, Sirup Chloramphenicol, umumnya mengandung 25 mg/ml,

Sirup Ampicillin, umumnya mengandung 25 mg/ml, Sirup Amoxycillin, umumnya mengandung

25 mg/ml, Sirup Cloxacillin, umumnya mengandung 25 mg/ml.

Dry Syrup atau sirup kering, berupa campuran obat dengan sakarosa, harus dilarutkan dalam

jumlah air tertentu sebelum dipergunakan. Keuntungan sirup kering dari pada sirup cairan,

biasanya sirup kering dapat tahan disimpan lebih lama. Contohnya Ampicillin trihydrate “dry

syrup”, ekivalen dengan 25 mg/ml sirup cairan kalau sudah dilarutkan dalam jumlah air yang

ditentukan.

2.      Flavored Syrup (sirup korigen/pembawa),

Biasanya tidak digunakan untuk tujuan medis, namun mengandung berbagai bahan aromatis

atau rasa yang enak dan digunakan sebagai larutan pembawa atau pemberi rasa pada berbagai

sediaan farmasi lainnya, misalnya sebagai penutup rasa pahit pada Vitamin B Kompleks yang

diberikan kepada bayi atau anak-anak. Sirup golongan ini, mengandung berbagai bahan

tambahan, misalnya bahan antioksidan (antioxidant agent), pengawet (preservative agent),

pewarna (coloring agent), pemberi rasa (flavoring agent), dan bahan pelarut (diluting agent).

Sirup ini, ditambahkan sebagai korigens rasa untuk obat minum, cukup dalam jumlah 10-20 ml

untuk tiap 100 ml larutan obat.

Sirup yang sering dipakai sebagai korigens-rasa, yaitu Sirup Simpleks, mengandung 65%

gula dalam larutan nipagin 0,25% b/v, Sirup Aurantii, terutama untuk bahan obat yang rasanya

pahit, dan Sirup Rubi Idaei, terutama untuk bahan obat yang rasanya asam.

Komponen Syrup

1.      Pemanis

Pemanis berfungsi untuk memperbaiki rasa dari sediaan. Dilihat dari kalori yang dihasilkan

dibagi menjadi pemanis berkalori tinggi dan pemanis berkalori rendah. Adapun pemanis

berkalori tinggi misalnya sorbitol, sakarin dan sukrosa sedangkan yang berkalori rendah seperti

laktosa.

2.      Pengawet Antimikroba

Digunakan untuk menjaga kestabilan obat dalam penyimpanan agar dapat bertahan lebih

lama dan tidak ditumbuhi oleh mikroba atau jamur.

3.      Perasa dan Pengaroma

Hampir semua sirup disedapkan dengan pemberi rasa buatan atau bahan-bahan yang berasal

dari alam untuk membuat syrup mempunyai rasa yang enak karena sirup adalah sediaan cair,

pemberi rasa ini harus mempunyai kelarutan dalam air yang cukup. Pengaroma ditambahkan ke

dalam syrup untuk memberikan aroma yang enak dan wangi. Pemberian pengaroma ini harus

sesuai dengan rasa sediaan syrup, misalkan syrup dengan rasa jeruk diberi aroma citrus.

4.      Pewarna

Pewarna yang digunakan umumnya larut dalam air dan tidak bereaksi dengan komponen

lain dalam syrup dan warnanya stabil dalam kisaran pH selama penyimpanan. Penampilan

keseluruhan dari sediaan cair terutama tergantung pada warna dan kejernihan. Pemilihan warna

biasanya dibuat konsisten dengan rasa. Ada beberapa alasan mengapa sirup itu berwarana, yaitu:

lebih menarik dalam faktor estetikanya serta untuk menutupi kestabilan fisik obat. Juga banyak

sediaan syrup, terutama yang dibuat dalam perdagangan mengandung pelarut-pelarut khusus,

pembantu kelarutan, pengental dan stabilisator.

Keuntungan dan Kerugian Sediaan Syrup

Adapun keuntungan dari sediaan sirup yaitu :

1.      Merupakan campuran yang homogen.

2.      Dosis dapat diubah-ubah dalam pembuatan.

3.      Obat lebih mudah diabsorbsi.

4.      Mempunyai rasa manis.

5.      Mudah diberi bau-bauan dan warna sehingga menimbulkan daya tarik untuk anak.

6.      Membantu pasien yang mendapat kesulitan dalam menelan obat tablet.

Sedangkan kerugian dari sediaan sirup yaitu :

1.      Ada obat yang tidak stabil dalam larutan.

2.      Volume dan bentuk larutan lebih besar.

3.      Ada yang sukar ditutupi rasa dan baunya dalam sirup.

Sifat Fisika Kimia Sirup

1.      Viskositas

Viskositas atau kekentalan adalah suatu sifat cairan yang berhubungan erat dengan

hambatan untuk mengalir. Kekentalan didefinisikan sebagai gaya yang diperlukan untuk

menggerakkan secara berkesinambungan suatu permukaan datar melewati permukaan datar

lainnya dalam kondisi mapan tertentu bila ruang diantara permukaan tersebut diisi dengan cairan

yang akan ditentukan kekentalannya. Untuk menentukan kekentalan, suhu zat uji yang diukur

harus dikendalikan dengan tepat, karena perubahan suhu yang kecil dapat menyebabkan

perubahan kekentalan yang berarti untuk pengukuran sediaan farmasi. Suhu dipertahankan dalam

batas tidak lebih dari 0,1 C.

2.      Uji mudah tidaknya dituang

Uji mudah tidaknya dituang adalah salah satu parameter kualitas sirup. Uji ini berkaitan erat

dengan viskositas. Viskositas yang rendah menjadikan cairan akan semakin mudah dituang dan

sebaliknya. Sifat fisik ini digunakan untuk melihat stabilitas sediaan cair selama

penyimpanan.Besar kecilnya kadar suspending agent berpengaruh terhadap kemudahan sirup

untuk dituang. Kadar zat penstabil yang terlalu besar dapat menyebabkan sirup kental dan sukar

dituang.

3.      Uji Intensitas Warna

Uji intensitas warna dilakukan dengan melakukan pengamatan pada warna sirup mulai

minggu 0-4. Warna yang terjadi selama penyimpanan dibandingkan dengan warna pada minggu

0. Uji ini bertujuan untuk mengetahui perubahan warna sediaan cair yang disimpan Selama

waktu tertentu.

Pembuatan Sirup

Kecuali dinyatakan lain, Sirup dibuat dengan cara sebagai berikut : Buat cairan untuk sirup,

panaskan, tambahkan gula, jika perlu didihkan hingga larut. Tambahkan air mendidih

secukupnya hingga diperoleh bobot yang dikehendaki, buang busa yang terjadi, serkai.

Pada pembuatan sirup dari simplisia yang mengandung glukosida antrakinon, di

tambahkan natrium karbonat sejumlah 10% bobot simplisia. Pada pembuatan sirop simplisia

untuk persediaan di tambahkan Nipagin 0,25% b/v atau pengawet yang cocok.sirop disimpan

dalam wadah tertutup rapar,dan di tempat yang sejuk.

Metode kerja pembuatan sirup yaitu sebagai berikut:

1.      Melarutkan bahan- bahan dengan bantuan pemanasan

2.      Sirup yang dibuat dengan cara ini apabila dibutuhkan pembuatan sirup secepat mungkin,

komponen sirup tidak rusak atau menguap oleh pemanasan. Pada cara ini umumnya gula

ditambahkan ke air yang dimurnikan dan dipanaskan sampai larut. Contoh : sirup akasia, sirup

cokelat

3.      Melarutkan bahan-bahan dengan pengadukan tanpa pemanasan

Metode ini dilakukan untuk menghindari panas yang merangsang inverse sukrosa. Prosesnya

membutuhkan waktu yang lebih lama tetapi mempunyai kestabilan yang maksimal. Bila bahan

padat akan ditambahkan ke sirup, yang paling baik adalah dengan melarutkannya dalam

sejumlah air murni dan kemudian larutan tersebut digabungkan ke dalam sirup. Contoh : sirup

ferro sulfat.

Penambahan sukrosa pada cairan obat yang dibuat atau pada cairan yang diberi rasa

(Colatura)

Ada kalanya cairan obat seperti tingtur atau ekstrak cair digunakan sebagai sumber obat

dalam pembuatan sirup. Banyak tingtur dan ekstrak seperti itu mengandung bahan-bahan yang

larut dalam alcohol dan dibuat dengan pembawa beralkohol atau hidroalkohol. Jika komponen

yang larut dalam alcohol dibutuhkan sebagai bahan obat dalam pembuatan sirup, beberapa cara

kimia umum dapat dilakukan agar bahan-bahan tersebut larut dalam air, campuran dibiarkan

sampai zat-zat yang tidak larut dalam air terpisah sempurna dan menyaringnya dari campuran.

Filtratnya adalah cairan obat yang kepadanya kemudian ditambahkan sukrosa dalam sediaan

sirup. Pada kondisi lain, apabila tingtur dan ekstrak kental dapat bercampur dengan sediaan

berair, ini dapat ditambahkan langsung ke sirup biasa atau sirup pemberi rasa sebagai obat.

Contoh : Sirup sena.

a.       Maserasi, Perkolasi, dan Infundasi

Adalah cara penarikan sari dari simplisia dengan cara merendam simplisia tersebut dalam

cairan penyari pada suhu biasa yaitu pada suhunya 15-25 0C. Contoh : Sirupus Rhei, Althaeae

sirup

Perkolasi ialah suatu cara penarikan, memakai alat yang disebut perkolator, yang

simplisianya terendam dalam cairan penyari dimana zat-zatnya terlarut dan larutan tersebut akan

menetes secara beraturan keluar sampai memenuhi syarat-syarat yang telah

ditetapkan.Contoh :Sirupus cinnamomi, sirup aurantii corticis. Infundasi adalah ekstraksi

ekstraksi cara panas yang dilakukan dengan menggunakan pelarut air pada temperatur 90° C

selama 15 menit.

b.      Persyaratan Mutu Dalam Pengerjaan Sirup

Pada pembuatan sirup dari simplisia yang mengandung glikosida antrakinon di tambahkan

Na2CO3 sejumlah 10% bobot simplisia. Kecuali dinyatakan lain, pada pembuatan sirup

simplisia untuk persediaan ditambahkan metil paraben 0,25 % b/v atau pengawet lain yang

cocok. Kadar gula dalam sirup pada suhu kamar maksimum 66 % sakarosa, bila lebih tinggi akan

terjadi pengkristalan, tetapi bila lebih rendah dari 62 % sirup akan membusuk.

Bj sirup kira-kira 1,3. Pada penyimpanan dapat terjadi inversi dari sakarosa ( pecah menjadi

glukosa dan fruktosa ) dan bila sirup yang bereaksi asam inversi dapat terjadi lebih cepat.

Pemanasan sebaiknya dihindari karena pemanasan akan menyebabkan terjadinya gula invert.

Gula invert adalah gula yang terjadi karena penguraian sakarosa yang memutar bidang polarisasi

kekiri. Gula invert tidak dikehendaki dalam sirup karena lebih encer sehingga mudah berjamur

dan berwarna tua (terbentuk karamel), tetapi mencegah terjadinya oksidasi dari bahan obat.

Pada sirup yang mengandung sakarosa 62 % atau lebih, sirup tidak dapat ditumbuhi jamur,

meskipun jamur tidak mati. Bila kadar sakarosa turun karena inversi, maka jamur dapat tumbuh.

Bila dalam resep, sirup diencerkan dengan air dapat pula ditumbuhi jamur. Untuk mencegah

sirup tidak menjadi busuk, dapat ditambahkan bahan pengawet misalnya nipagin. Kadang-

kadang gula invert dikehendaki adanya misalnya dalam pembuatan sirupus Iodeti ferrosi.Hal ini

disebabkan karena sirup merupakan media yang mereduksi, mencegah bentuk ferro menjadi

bentuk ferri. Gula invert disini dipercepat pembuatannya dengan memanaskan larutan gula

dengan asam sitrat.

Bila cairan hasil sarian mengandung zat yang mudah menguap maka sakarosa dilarutkan

dengan pemanasan lemah dan dalam botol yang tertutup, seperti pada pembuatan Thymi sirupus

dan Thymi compositus sirupus, aurantii corticis sirupus. Untuk cinnamomi sirupus sakarosa

dilarutkan tanpa pemanasan. Maksud menyerkai pada sirup adalah untuk memperoleh sirup yang

jernih. Untuk penjernihan Sirup, dapat dilakukan dengan beberapa cara yaitu : Menambahkan

kocokan zat putih telur segar pada sirup . Didihkan sambil diaduk, zat putih telur akan

menggumpal karena panas. Menambahkan bubur kertas saring lalu didihkan dan saring kotoran

sirup akan melekat ke kertas saring.

Kestabilan Sirup dalam Penyimpan

Cara memasukkan sirup ke dalam botol penting untuk kestabilan sirup dalam penyimpanan,

supaya awet (tidak berjamur ) sebaiknya sirup disimpan dengan cara :

1.      Sirup yang sudah dingin disimpan dalam wadah yang kering. Tetapi pada pendinginan ada

kemungkinan terjadinya cemaran sehingga terjadi juga penjamuran.

2.      Mengisikan sirup panas-panas kedalam botol panas ( karena sterilisasi ) sampai penuh sekali

sehingga ketika disumbat dengan gabus terjadi sterilisasi sebagian gabusnya, lalu sumbat gabus

dicelup dalam lelehan parafin solidum yang menyebabkan sirup terlindung dari pengotoran udara

luar.

3.      Sterilisasi sirup, disini harus diperhitungkan pemanasan 30 menit apakah tidak berakibat

terjadinya gula invert. Maka untuk kestabilan sirup, FI III juga menuliskan tentang panambahan

metil paraben 0,25% atau pengawet lain yang cocok.

Dari ketiga cara memasukkan sirup ke dalam botol ini yang terbaik adalah cara ketiga.

Dalam ilmu farmasi sirup banyak digunakan karena dapat berfungsi sebagai obat, misalnya :

chlorfeniramini maleatis sirupus, Corigensia saporis, misalnya : sirupus simplex, Corigensia

odoris, misalnya : sirupus aurantii, Corigensia coloris, misalnya : sirupus Rhoedos, sirupus rubi

idaei. Pengawet, misalnya sediaan dengan bahan pembawa sirup karena konsentrasi gula yang

tinggi mencegah pertumbuhan bakteri.

Untuk penyimpanan sediaan sirup yaitu dalam wadah tertutup rapat dan di tempat sejuk.

Sedangkan untuk penetapan kadar sakarosa mtode kerjanya yaitu

1.      Timbang seksama + 25 gram sirup dalam labu terukur 100 ml, tambahkan 50 ml air dan sedikit

larutan Aluminium hidroksida p. Tambahkan larutan timbal ( II ) sub asetat p tetes demi tetes

hingga tetes terakhir tidak menimbulkan kekeruhan.

2.      ]Tambahkan air secukupnya hingga 100,0 ml saring, buang 10 ml filtrat pertama. Masukkan +

45,0 ml filtrat kedalam labu tentukur 50 ml, tambahkan campuran 79 bagian volume asam

klorida p dan 21 bagian vol. Air secukupnya hingga 50,0 ml. Panaskan labu dalam tangas air

pada suhu antara 68 o dan 70 oC selama 10 menit, dinginkan dengan cepat sehingga suhu lebih

kurang 20 oC.

3.      Jika perlu hilangkan warna dengan menggunakan tidak lebih dari 100 mg arang penyerap.

4.      Ukur rotasi optik larutan yang belum di inversi dan sesudah inversi menggunakan tabung 22,0

cm pada suhu pengukur yang sama antara 10 o dan 25 o C. Hitung kadar dalam %, C12H22O11

dengan rumus :

C = 300 x ( α1 - α2 )

( 144 - 0,5 t )

C = Kadar sacharosa dalam %

α1 = rotasi optik larutan yang belum di inversi

α2 = rotasi optik larutan yang sudah di inversi

t = suhu pengukuran

Contoh-contoh Sediaan Sirup

1.      Ferrosi Iodidi Sirupus

Cara pembuatan : 20 bagian ferrum pulveratum dicampur dengan 60 bagian air, tambahkan

41 bagian Iodium sedikit demi sedikit sambil digerus. Setelah warna coklat hilang maka larutan

disaring, dimasukkan kedalam larutan ½ bagian acidum citricum dan 600 bagian sakarosa dalam

200 bagian air panas. Untuk mencegah terjadinya oksidasi dari ferro Iodida maka ujung corong

masuk kedalam larutan sakarosa. Sisa serbuk besi pada kertas saring dicuci dengan air sampai

diperoleh 1000 bagian sirup.

Guna acidum citricum adalah untuk mempercepat inversi sakarosa, menjadi glukosa dan

fruktosa yang merupakan reduktor kuat yang berguna untuk mencegah oksidasi ferro lodidum.

Ferro Iodidum selalu dibuat baru.

2.      Sirupus Simplex = Sirup Gula

Cara pembuatan : larutkan 65 bagian sakarosa dalam larutan metil paraben 0,25 %

secukupnya hingga diperoleh 100 bagian sirup

Pemerian : cairan jernih, tidak berwarna

Penyimpanan : dalam wadah tertutup rapat, di tempat sejuk

3.      Auranti Sirupi = Sirup Jeruk Manis

Cara pembuatan : campur 10 bagian kulit buah jeruk manis yang telah dipotong kecil-kecil

dengan 20 bagian larutan metil paraben 0,25%. Biarkan dalam tempat tertutup selama 12 jam.

Pindahkan ke dalam perkolator, perkolasi dengan larutan metil paraben 0,25% secukupnya

hingga diperoleh 37 bagian perkolat. Tambahkan 63 bagian gula pada suhu kamar atau pada

pemanasan perlahan-lahan dalam tempat tertutup hingga diperoleh 100 bagian sirup

Pemerian : cairan kental, jernih, warna coklat, bau khas aromatik.

4.      Sirupus Thymi = Sirup Thymi

Cara pembuatan : campurlah 15 bagian herba timi dengan air sesukupnya dan diamkan 12

jam dalam bejana tertutup. Masukan dalam perkolatordan sari dengan air, perkolat dipanasi

sampai 90 0C dan diserkai hingga diperoleh 36 bagian hasil perkolat. Masukan dalam bejana

tertutup dan tambahkan 64 bagian gula panaskan dengan pemanasan lemah hingga diperoleh 100

bagian sirup.

Sirup-sirup yang tercantum dalam FI ed III yaitu :

1.      Chlorpheniramini maleatis sirupus

2.      Cyproheptadini hydrochloridi sirupus

3.      Dextrometorphani hydrobromidi sirupus

4.      Piperazini citratis sirupus

5.      Prometazini hydrochloridi sirupus

6.      Methidilazini hydrochloridi sirupus

7.     Sirupus simplex yang dibuat dengan melarutkan 65 bagian sacharosa dalam larutan metil

paraben secukupnya hingga diperoleh 100 bagian sirup.

8.     Dalam perdagangan dikenal “dry syrup” yaitu syrup berbentuk kering yang kalau akan dipakai

ditambahkan sejumlah pelarut tertentu atau aqua destilata, biasanya berisi zat yang tidak stabil

dalam suasana berair. (Akfar PIM/2010)

CefadroxilFrom Wikipedia, the free encyclopedia

Cefadroxil

Systematic (IUPAC) name

,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Clinical data

Trade names Generic

AHFS/Drugs.com monograph

MedlinePlus a682730

Legal status ℞ (Prescription only)

Routes ofadministration

Oral

Pharmacokinetic data

Protein binding plasma protein

Metabolism unknown

Biological half-life 1.5 hours

Identifiers

CAS Registry Number 66592-87-8 

ATC code J01   DB05   

PubChem CID: 47964

DrugBank DB01140 

ChemSpider 43629 

UNII 280111G160 

KEGG D02353 

ChEBI CHEBI:53667 

ChEMBL CHEMBL1644 

Chemical data

Formula C16H17N3O5S

Molecular mass 363.389 g/mol

SMILES   [show]   

InChI   [show]   

(what is this?) (verify)

Cefadroxil (formerly trademarked as Duricef) is a broad-spectrum antibiotic of the cephalosporin type, effective in Gram-positive and Gram-negative bacterial infections. It is a bactericidal antibiotic.

Contents

1     General use    2     Spectrum of bacterial resistance and susceptibility    3     Pharmacokinetics    4     Dosage    5     Side effects    6     Dental use    7     Veterinary use    8     References   

General use

Cefadroxil is a first-generation cephalosporin antibacterial drug that is the para-hydroxy derivative of cefalexin, and is used similarly in the treatment of mild to moderate susceptible

infections such as the bacterium Streptococcus pyogenes, causing the disease popularly called strep throat or streptococcal tonsillitis, urinary tract infection, reproductive tract infection, and skin infections.

Spectrum of bacterial resistance and susceptibility

Cefadroxil has a broad spectrum of activity and has been effective in treating bacteria responsible for causing tonsillitis, and infections of the skin and urinary tract. The following represents MIC susceptibility data for a few medically significant microorganisms.

Escherichia coli: 8 μg/ml Staphylococcus aureus: 1 – 2 μg/ml Streptococcus pneumoniae: ≤1 – >16 μg/ml

[1]

Pharmacokinetics

Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/ml, respectively, are obtained after 1.5 to 2.0 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil. About 20% of cefadroxil is reported to be bound to plasma proteins. Its plasma half-life is about 1.5 hours and is prolonged in patients with renal impairment.

Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk. More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/ml have been reported after a dose of 500 mg. Cefadroxil is removed by haemodialysis.

Dosage

Cefadroxil is given by mouth, and doses are expressed in terms of the anhydrous substance; 1.04 g of cefadroxil monohydrate is equivalent to about 1 g of anhydrous cefadroxil.

Side effects

The most common side effects of cefadroxil are diarrhea (which, less commonly, may be bloody), nausea, upset stomach, and vomiting. Other side effects include[2] rashes, hives, and itching.

Dental use

Cefadroxil is used as an antibiotic prophylaxis before dental procedures, for patients allergic to penicillins.

Veterinary use

It can be used for treating infected wounds on animals. Usually in powder form mixed with water, it has a color and smell similar to Tang. Given orally to animals, the amount is dependent on their weight and severity of infection.

Dry syrup Production

Dry syrup

A dry pharmaceutical syrup may be defined as a finely divided insoluble particle ranging from 0.5-5 μ, 

which   is   to  be  distributed   in  a   suitable  vehicle  Dry   syrups  are   the   solid  dosage   form that   can  be 

reconstituted by the addition of water to administer by the oral route. Mostly antibiotics are available in 

dry syrup form. Besides, some moisture sensitive and pediatric drugs are also available in the form of 

dry syrup.

Production of Dry Syrup

Mostly antibiotics are available in dry syrup form. Dry syrup at Renata is manufactured in three methods 

namely: 

  Direct Mixing, 

  Dry Granulation (Slugging) and 

  Wet Granulation (wet massing).

The flow chart of the above mentioned methods are as follows.

Sealing & Checking

Packaging

Sieving

Blending

Filling

Labeling

Flow Chart of Direct Mixing

Flow chart for Wet granulation

Condition for manufacturing Dry Syrup:

  Relative humidity: Not more than 60%.

  Temperature: Below 250C

  All relevant materials are removed

  Equipment is cleaned

  Balanced is calibrate 

  Bottle drying date

When these condition are fulfilled the area is ready for filling of dry syrup and sighed by :

 Production officer

 Checked by QA officer  

Machines used in Dry Syrup:

1.      Frewitt-Zimmer Mann Chimermann Granulator, Source: Germany.

2.      Karl-Kold Fluid Granulator, Source: Germany.

3.      Ciliotta Bottle Sealing Machine, Source: France.

4.      Macofar Automatic Bottle Filling and Sealing Machine, Source: Italy.

5.      Fitz mill (Sugar Crushing machine), Source: USA.

6.      Multimilling Machine, Source: Bangladesh

7.      Hutt Compactor, Source: Germany

8.      Roller Compactor, Source: India.

9.      Blender Machine (400 kg)

10.  Left Gun Bottle Filling Machine, Source: USA.

Monographs: Dosage forms: General monographs: Liquid preparations for oral use

This monograph does not apply to liquids intended for oromucosal administration (for example, gargles and mouthwashes).

DefinitionLiquid preparations for oral use are usually solutions, emulsions or suspensions containing one or more active ingredients in a suitable vehicle; they may in some cases consist simply of a liquid active ingredient used as such. Liquid preparations for oral use are either supplied in the finished form or, with the exception of Oral emulsions, may also be prepared just before issue for use by dissolving or dispersing granules or powder in the vehicle stated on the label.

The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use of the preparation. Liquid preparations for oral use may contain suitable antimicrobial preservatives, antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and authorized colouring matter.

Liquid preparations for oral use may be supplied as multidose or as single-dose preparations. Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 mL or multiples thereof, or an oral syringe for other volumes or, for Oral drops, a suitable dropper.

Additional information. Liquid preparations for oral use are often the dosage form of choice for paediatric use.

Owing to the wide range of liquid preparations for oral use and their long history of use, a variety of terms has been used to describe different members of this category of preparation. These terms, which are not mutually exclusive and the definitions of which have changed over time, include elixirs, linctuses, milks, mixtures and syrups. Such terms are still used within the titles of certain specific, long-established, traditional preparations (for example, ephedrine elixir, codeine linctus, acid gentian mixture). With such exceptions, however, it is recommended that the titles of liquid dosage forms for oral use are based on the terms used as sub-monograph headings in this general monograph. The term syrup (denoting a solution containing a high proportion of sucrose) is used, inter alia, for certain solutions (for example, black currant syrup, lemon syrup) that are used as vehicle ingredients for their sweetening and flavouring properties. Such syrups are not dosage forms in the pharmacopoeial sense: they do not contain any active ingredient and are not intended to be administered as such.

Oral solutions containing one or more active ingredients dissolved in a vehicle containing a high proportion of sucrose or a suitable polyhydric alcohol or alcohols and which may contain ethanol have traditionally been called elixirs. Viscous oral solutions containing one or more active ingredients dissolved in a vehicle containing a high proportion of sucrose, other sugars or a

suitable polyhydric alcohol or alcohols and which are intended for use in the treatment or relief of cough have traditionally been called linctuses. They are intended to be sipped and swallowed slowly without the addition of water.

ManufactureThe manufacturing process for liquid preparations for oral use should meet the requirements of Good Manufacturing Practice (GMP).

The following information is intended to provide broad guidelines concerning the critical steps to be followed during production of liquid preparations for oral use.

In the manufacture of liquid preparations for oral use, measures are taken to:

• ensure that all ingredients are of appropriate quality • minimize the risk of microbial contamination (see recommendations in chapter MICROBIOLOGICAL QUALITY OF NON-STERILE PRODUCTS: RECOMMENDED ACCEPTANCE CRITERIA FOR PHARMACEUTICAL PREPARATIONS of the supplementary information section.); • minimize the risk of cross-contamination

During the development of a preparation, the formulation for which contains one or more antimicrobial preservatives, the effectiveness of the chosen preservative system shall be demonstrated to the satisfaction of the relevant regulatory authority.

Appropriate measures should also be taken to optimize the stability of the active ingredient(s) in liquid formulations including those prepared from powder or granules. Additional measures should be taken so that, when stored under the conditions stated on the label, oral solutions are not subject to precipitation and oral suspensions are not subject to fast sedimentation, lump formation or caking.

During development of a single-dose liquid preparation for oral use it shall be demonstrated that the nominal content can be withdrawn from the container.

In the production of liquid preparations for oral use containing dispersed particles, measures are taken to ensure a suitable and controlled particle size and, where appropriate, crystal structure (polymorphic and/or solvated forms) with regard to the intended use.

Throughout manufacturing, certain procedures should be validated and monitored by carrying out appropriate in-process controls. These should be designed to guarantee the effectiveness of each stage of production. In-process controls during the manufacture of oral liquids should include pH and fill volume. The validation of the manufacturing process and the in-process controls are documented.

Safety concernsAn important aspect of Good Manufacturing Practice for all pharmaceutical products is assuring the quality of all the starting materials used. The need for analytical testing to check the identity

and quality of starting materials is explained in detail in section 14 of the current WHO GMP guidelines1. Failure to ensure that starting materials are of the required quality can have very serious consequences.

Increasingly countries are dependent on the importation of starting materials for use in the production of medicines. Starting materials often change hands many times before reaching the manufacturer of the final marketed product and there are many opportunities for the material to undergo relabelling along the distribution and trade chain (see WHO Guideline on Good Trade and Distribution Practices for Pharmaceutical Starting Materials1). As a result, starting materials required for production of pharmaceutical products can become contaminated or materials may be supplied that no longer correspond to what is stated on the label in terms of quality or identity, either accidentally or as a result of negligence and sometimes fraud.

The most documented incidents of contamination involve liquid preparations for oral use manufactured with excipients such as glycerol and propylene glycol that have been contaminated, adulterated or mixed up with diethylene glycol. Such incidents have been responsible for hundreds of deaths throughout the world (see, for example, editorial in WHO Bulletin 2001, 79(2)). Ingestion of diethylene glycol often leads to death through kidney failure.

1 For the current edition of WHO guidelines, please consult the WHO Medicines web site: http://www.who.int/medicines/en/.

Uniformity of massLiquid preparations for oral use that are presented as single-dose preparations comply with the following test. Weigh individually the contents of 20 containers, emptied as completely as possible, and determine the average mass. Not more than 2 of the individual masses deviate by more than 10% from the average mass and none deviates by more than 20%.

Uniformity of mass of doses delivered by the measuring deviceThe measuring device provided with a multidose liquid preparation for oral use complies with the following test. Weigh individually 20 doses taken at random from one or more multidose containers with the measuring device provided and determine the individual and average masses. Not more than two of the individual masses deviate by more than 10% from the average mass and none deviates by more than 20%.

ContainersThe containers should be made of material that will not adversely affect the quality of the preparation by, for example, leaching or sorption. Liquid preparations for oral use that contain light-sensitive active ingredients are supplied in containers that are light-resistant.

Except where indicated in the individual monograph, containers should be made from material that is sufficiently transparent to permit the visual inspection of the contents.

If the preparation contains volatile ingredients, the liquid preparation for oral use should be kept in a tightly closed container.

LabellingEvery pharmaceutical preparation must comply with the labelling requirements established under Good Manufacturing Practice.

The label should include:

(1) the name of the pharmaceutical product;(2) the name(s) of the active ingredients; INNs should be used wherever possible;(3) the amount of active ingredient in a suitable dose-volume;(4) the name and concentration of any antimicrobial preservative and the name of any other excipient;(5) the batch (lot) number assigned by the manufacturer;(6) the expiry date and, when required, the date of manufacture;(7) any special storage conditions or handling precautions that may be necessary;(8) directions for use, warnings, and precautions that may be necessary;(9) the name and address of the manufacturer or the person responsible for placing the product on the market.

If the Liquid preparation for oral use is supplied as granules or powder to be constituted just before issue for use, the label should include:

(1) that the contents of the container are granules or powder for the preparation of an oral liquid;(2) the strength as the amount of the active ingredient in a suitable dose-volume of the constituted preparation;(3) the directions for preparing the oral liquid including the nature and quantity of liquid to be used;(4) the storage conditions and shelf-life of the constituted preparation.

Requirements for specific types of liquid preparations for oral use

Oral solutions

DefinitionOral solutions are clear Liquid preparations for oral use containing one or more active ingredients dissolved in a suitable vehicle.

Visual inspectionInspect the solution. It should be clear and free from any precipitate. A change in colour or cloudiness of solutions may indicate chemical degradation or microbial contamination.

Oral suspensions

DefinitionOral suspensions are Liquid preparations for oral use containing one or more active ingredients suspended in a suitable vehicle. For oral suspensions containing more than one active ingredient, some of the active ingredients may be in solution.

Oral suspensions may show a sediment which is readily dispersed on shaking to give a uniform suspension which remains sufficiently stable to enable the correct dose to be delivered.

Visual inspectionInspect the suspension. Evidence of physical instability is demonstrated by the formation of flocculants or sediments that do not readily disperse on gentle shaking. A change in colour may indicate chemical degradation or microbial contamination.

Uniformity of content. For oral suspensions that are presented as single-dose preparations and that contain less than 5 mg of active ingredient per dose or in which the active ingredient is less than 5% of the total weight per dose, carry out the following test. Shake and empty each container as completely as possible and carry out the test as described under 5.1 Uniformity of content for single-dose preparations. In such cases, the test for Uniformity of mass prescribed above is not required.

LabellingThe label on the container should include a direction that the bottle should be shaken before use.

Oral emulsions

DefinitionOral emulsions are Liquid preparations for oral use containing one or more active ingredients. They are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in Oral emulsions.

Oral emulsions may show evidence of phase separation but are readily redispersed on shaking.

Visual inspectionInspect the emulsion. Evidence of physical instability is demonstrated by phase separation that is not readily reversed on gentle shaking. A change in colour of emulsions may indicate chemical degradation or microbial contamination.

ContainersWhen issued for use, Oral emulsions should be supplied in wide-mouthed bottles.

LabellingThe label on the container should include a direction that the bottle should be shaken before use.

Oral drops

DefinitionOral drops are Liquid preparations for oral use that are intended to be administered in small volumes with the aid of a suitable measuring device. They may be solutions, suspensions or emulsions.

Visual inspectionInspect the drops. Drops that are solutions should be clear and free from any precipitate. Evidence of physical instability of drops that are suspensions is demonstrated by the formation of flocculants or sediments that do not readily disperse on gentle shaking. Evidence of physical instability of drops that are emulsions is demonstrated by phase separation that is not readily reversed on gentle shaking. A change in colour (or cloudiness of solutions) may indicate chemical degradation or microbial contamination of the drops.

Dose and uniformity of dose of oral dropsInto a suitable, graduated cylinder, introduce by means of the dropping device the number of drops usually prescribed for one dose or introduce by means of the measuring device the usually prescribed quantity. The dropping speed does not exceed 2 drops per second. Weigh the liquid, repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10 masses are obtained. No single mass deviates by more than 10% from the average mass. The total of 10 masses does not differ by more than 15% from the nominal mass of 10 doses. If appropriate, measure the total volume of 10 doses. The volume does not differ by more than 15% from the nominal volume of 10 doses.

ContainersOral drops are normally supplied in suitable multidose containers that allow successive drops of the preparation to be administered.

Powders for oral solutions, oral suspensions or oral drops

Presentations of powder (usually single-dose presentations, for example, a small sachet) that are intended to be issued to the patient as a powder, to be taken in or with water or another suitable liquid, are outside the scope of this general monograph. Such preparations are controlled by the monograph for Oral powders.

DefinitionPowders for oral solutions, suspensions or drops are multidose preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, if necessary, authorized colouring matter and flavouring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking.

After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral solutions, Oral suspensions or Oral drops, as appropriate.

ManufactureIn the manufacture of powders for oral solutions, suspensions or drops, the components of the powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed masses of the sieved components, preferably of a narrow particle size distribution, are then transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually occurs when emptying the mixer container and when the powder mixture is dosed into

the containers. Ensuring the suitability of the mixing equipment and the dosing devices is, therefore, critical.

Visual inspectionInspect the powder. Evidence of physical instability is demonstrated by noticeable changes in physical appearance, including texture (for example, clumping). A change in colour may indicate chemical degradation or microbial contamination.

Granules for oral solutions or suspensions

Presentations of granules that are intended to be issued to the patient as granules to be swallowed as such, to be chewed, or to be taken in or with water or another suitable liquid, are outside the scope of this general monograph.

DefinitionGranules for oral solutions or suspensions are multidose preparations consisting of solid, dry aggregates of powder particles sufficiently resistant to withstand handling. They contain one or more active ingredients with or without excipients and, if necessary, authorized colouring matter and flavouring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking.

After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral solutions or Oral suspensions, as appropriate.

Visual inspectionInspect the granules. Evidence of physical instability is demonstrated by noticeable changes in physical appearance, including texture (for example, clumping of granules, presence of loose powder). A change in colour may indicate chemical degradation or microbial contamination.

Monographs: Dosage forms: General monographs: Oral powders

The requirements of this monograph do not necessarily apply to powders to be used for the preparation of oral solutions or suspensions.

DefinitionOral powders are preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, if necessary, authorized colouring matter and flavouring substances. They are generally administered in or with water or another suitable liquid. They may also be swallowed directly. They are presented as single-dose or multidose preparations.

Each dose of a single-dose powder is enclosed in an individual container, for example a packet, a sachet or a vial. Multidose oral powders require the provision of a measuring device capable of delivering the quantity prescribed.

ManufactureThe manufacturing process for oral powders should meet the requirements of Good Manufacturing Practice (GMP).

The following information is intended to provide broad guidelines concerning the critical steps to be followed during production of oral powders.

In the manufacture of oral powders, measures are taken to:

• ensure that there is a suitable particle size range with regard to the intended use;• minimize the risk of microbial contamination;• minimize the risk of cross-contamination.

Appropriate measures should also be taken to counteract segregation of the components of the powder mixture. Segregation takes place whenever a free-flowing powder consisting of particles of a range of sizes is handled, including the mixing stage and emptying of the mixer container. The prime means to counteract segregation is to use components of similar particle size. In cases where the risk of segregation is significant, oral powders containing a low proportion of the active ingredient, for example, less than 5% of total mass, should preferably be prepared as single-dose preparations.

In the production of oral powders, the components of the powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed masses of the sieved components, preferably of a narrow particle size distribution, are then transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually occurs when emptying the mixer container and when the powder mixture is dosed into the containers. Ensuring the suitability of the mixing equipment and the dosing devices is therefore critical.

Throughout manufacturing certain procedures should be validated and monitored by carrying out appropriate in-process controls. These should be designed to guarantee the effectiveness of each stage of production. In-process controls during the manufacture of oral powders should include the dosing by mass of the powder into the containers.

The validation of the manufacturing process and the in-process controls are documented.

The intended mass of one dose of an oral powder should be at least 500 mg to minimize the effect of loss of powder when taken from a single-dose container or to allow a proper dosing when using a measuring device.

Visual inspectionInspect the powder, using at least 20 containers for single-dose preparations. Evidence of physical and/ or chemical instability is demonstrated by noticeable changes in physical appearance, including texture [e.g. clumping] or colour.

Uniformity of contentSee the general requirements 5.1 Uniformity of content for single-dose preparations. Single-dose oral powders with a content of active ingredient of less than 5 mg or less than 5% of the total mass comply with the test, unless otherwise specified in the individual monograph. If the preparation has more than one active ingredient, the requirement applies only to those active ingredients that fall into the above category.

Uniformity of massSee the general requirements 5.2 Uniformity of mass for single-dose preparations. Single-dose oral powders comply with the test. If the test for uniformity of content is prescribed for all active ingredients, the test for uniformity of mass is not required.

Uniformity of mass of doses delivered by the measuring deviceThe measuring device provided with a multidose oral powder complies with the test. Weigh individually 20 doses taken at random from one or more multidose containers with the measuring device provided and determine the individual and average masses. Not more than two of the individual masses deviate by more than 10% from the average mass and none deviates by more than 20%.

LabellingEvery pharmaceutical preparation must comply with the labelling requirements established under GMP.

The label should include:

(1) the name of the pharmaceutical product;(2) the name(s) of the active ingredients; INNs should be used wherever possible;(3) for single-dose preparations, the amount of the active ingredient(s) per container and for multidose preparations, the amount of active ingredient in a suitable quantity by weight;(4) the batch (lot) number assigned by the manufacturer;

(5) the expiry date and, when required, the date of manufacture;(6) any special storage conditions or handling precautions that may be necessary;(7) directions for use, warnings, and precautions that may be necessary;(8) the name and address of the manufacturer or the person responsible for placing the product on the market.

StorageIf the preparation contains volatile or hygroscopic ingredients, the oral powder should be kept in tightly closed container.

Requirements for specific types of oral powder

Effervescent powders

DefinitionEffervescent powders are presented as single-dose or multidose preparations and generally contain acidic substances and carbonates or hydrogen carbonates which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration.

StorageEffervescent powders should be kept in tightly closed containers.

Methods of Analysis: 5. Pharmaceutical technical procedures: 5.5 Dissolution test for solid oral dosage forms

2014-01

This text is based on the internationally-harmonized texts developed by the Pharmacopoeial Discussion Group (PDG). It has been developed in line with the style and requirements used in The International Pharmacopoeia. The additional section on monographs of The International Pharmacopoeia is not part of the PDG text.

For further guidance, see also the chapter Dissolution testing of tablets and capsules in the Supplementary Information section.

This test determines the amount of active ingredient(s) released from a solid oral dosage form, such as a tablet or a capsule, under controlled conditions using a known volume of dissolution medium within a predetermined length of time.

Basket apparatus. The assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparent material, which should not sorb, react or interfere with the dosage form, the active ingredient or the dissolution medium; a motor; a drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water-bath of any convenient size or heated by a suitable device such as a heating jacket to maintain the temperature inside the vessel at 37 ± 0.5 ºC during the test and to keep the dissolution medium in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the preparation and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom and a capacity of 1 litre. Its height is 160–210 mm and its inside diameter is 98 –106 mm. Its sides are flanged at the top. A fitted cover may be used to retard evaporation. If a cover is used it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of samples. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble that could affect the results. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at a specified rate within ± 4%.

Shaft and basket components of the stirring element are fabricated of stainless steel, type 316 or equivalent, to the specifications shown in Figure 1. A basket having a gold coating of about 2.5 µm (0.0001 inch) thick may be used. The dosage unit is placed in a dry basket at the beginning of each test. The distance between the inside bottom of the vessel and the bottom of the basket is maintained at 25 ± 2 mm during the test.

1) Screen with welded seam: 0.22–0.31 mm wire diameter with wire opening of 0.36–0.44 mm. After welding the screen may be slightly altered.

2) Maximum allowable runout at “A” is 1.0 mm when the part is rotated on centre line axis with basket mounted.

Figure 1. Basket stirring element

Dimensions in millimetres

A and B dimensions do not vary more than 0.5 mm when part is rotated on centre line axis. Tolerances are ± 1.0 mm unless otherwise stated.

Figure 2. Paddle stirring element.

Dimensions in millimetres

Paddle Apparatus. Use the assembly from Basket apparatus except that a paddle formed from a blade and a shaft is used as the stirring element. The shaft is positioned so that its axis is not more than 2 mm from the vertical axis of the vessel at any point and rotates smoothly without significant wobble that could affect the results. The vertical centre line of the blade passes through the axis of the shaft so that the bottom of the blade is flush with the bottom of the shaft. The paddle conforms to the specifications shown in Figure 2. The distance of 25 ± 2 mm between the bottom of the blade and the inside bottom of the vessel is maintained during the test. The metallic or suitably inert, rigid blade and shaft comprise a single entity. A suitable two-part detachable design may be used provided the assembly remains firmly engaged during the test. The paddle blade and shaft may be coated with a suitable coating so as to make them inert. The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material, such as not more than a few turns of wire helix, may be attached to dosage units that would otherwise float. An alternative sinker device is shown in Figure 3. Other validated sinker devices may be used.

Figure 3. Alternative sinker. Dimensions in millimeters.

Recommended procedure

Conventional-release (or immediate-release) dosage forms

Procedure. Place the stated volume of the dissolution medium (± 1%) in the vessel of the specified apparatus. Assemble the apparatus, equilibrate the dissolution medium to 37 ± 0.5 °C, and remove the thermometer. The test may also be carried out with the thermometer in place, provided it is shown that results equivalent to those obtained without the thermometer are obtained. Place one dosage unit in the apparatus, taking care to exclude air bubbles from the surface of the dosage unit. Operate the apparatus at the specified rate. Within the time interval specified, or at each of the times stated, withdraw a sample from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall. Where multiple sampling times are specified replace the samples

withdrawn for analysis with equal volumes of fresh dissolution medium at 37 °C or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in the calculation. Keep the vessel covered for the duration of the test and verify the temperature (37 ± 0.5 °C) of the medium at suitable times. Perform the analysis as directed in the individual monograph using a suitable assay method. Test samples are filtered immediately upon sampling using in-line filtration, unless filtration is demonstrated to be unnecessary. Use an inert filter that does not cause adsorption of the active substance or contain extractable substances that would interfere with the analysis. Centrifugation is not recommended unless validated for the specific test. The test is to be conducted with six dosage form units in parallel.

If automated equipment is used for sampling or the apparatus is otherwise modified, verification is necessary that the modified apparatus will produce results equivalent to those obtained with the apparatus described in this chapter.

Dissolution medium. A suitable dissolution medium is used. The volume specified refers to measurements made between 20 °C and 25 °C. If the dissolution medium is a buffered solution adjust the solution so that its pH is within 0.05 units of the specified pH. Dissolved gases can cause bubbles to form, which may change the results of the test. In such cases, dissolved gases must be removed prior to testing.1

1 One appropriate method of deaeration is as follows: heat the medium, while stirring gently, to about 41 °C, immediately filter under vacuum using a filter having a pore size of 0.45 µm or less, with vigorous stirring and continue stirring under vacuum for at least 5 min, preferably 15 min, until no more bubbles are observed. Other validated deaeration techniques for removal of dissolved gases may be used.

Time. Where a single time specification is given the test may be concluded in a shorter period if the requirement for minimum amount dissolved is met. Samples are to be withdrawn only at the stated times, within a tolerance of ± 2%.

Determine the quantity of active ingredient dissolved at the specified time(s) indicated in the individual monograph. The result should be expressed as a percentage of the content stated on the label of the dosage form.

Sustained-release solid dosage forms

Procedure. Proceed as described for conventional-release dosage forms.

Dissolution medium. Proceed as described for conventional-release dosage forms.

Time. The test-time points, generally 3, are expressed in hours.

Delayed-release, solid dosage forms

Procedure. Use method A or B

Method A

• Acid stage. Place 750 mL hydrochloric acid (0.1 mol/l) VS in the vessel and assemble the apparatus. Allow the medium to equilibrate to a temperature of 37 ± 0.5 °C. Place one dosage unit in the apparatus, cover the vessel and operate the apparatus at the specified rate. After 2 h of operation in hydrochloric acid (0.1 mol/l) VS withdraw a sample of the fluid and proceed immediately as directed under Buffer stage. Perform an analysis of the sample using a suitable assay method.

• Buffer stage. Complete the operations of adding and adjusting the pH within 5 min. With the apparatus operating at the rate specified add to the fluid in the vessel 250 mL of a 0.2 M solution of trisodium orthophosphate R that has been equilibrated to 37 ± 0.5 °C. Adjust, if necessary, with hydrochloric acid (~70 g) TS or sodium hydroxide (~80 g/l) TS to a pH of 6.8 ± 0.05. Continue to operate the apparatus for 45 min or for the specified time. At the end of the time period withdraw a sample of the fluid and perform the analysis using a suitable assay method.

Method B

• Acid Stage. Place 1000 mL of hydrochloric acid (0.1 mol/l) VS in the vessel and assemble the apparatus. Allow the medium to equilibrate to a temperature of 37 ± 0.5 °C. Place one dosage unit in the apparatus, cover the vessel and operate the apparatus at the specified rate. After 2 hours of operation in hydrochloric acid (0.1 mol/l) VS withdraw a sample of the fluid and proceed immediately as directed under Buffer stage. Perform an analysis of the sample using a suitable assay method.

• Buffer stage. For this stage of the procedure use buffer that has previously been equilibrated to a temperature of 37 ± 0.5 °C. Drain the acid from the vessel and add 1000 mL of pH 6.8 phosphate buffer, prepared by mixing three volumes of hydrochloric acid (0.1 mol/l) VS with one volume of a 0.20 M solution of trisodium orthophosphate R and adjusting, if necessary, with hydrochloric acid (~70 g/l) TS or sodium hydroxide (~80 g/l) TS to a pH of 6.8 ± 0.05. This may also be accomplished by removing from the apparatus the vessel containing the acid and replacing it with another vessel containing the buffer and transferring the dosage unit to the vessel containing the buffer. Continue to operate the apparatus for 45 minutes or for the specified time. At the end of the time period withdraw a sample of the fluid and perform the analysis using a suitable assay method.

Time. All test times stated are to be observed within a tolerance of ± 2%, unless otherwise specified.

Acceptance criteria

Conventional-release (or immediate-release) dosage forms

Unless otherwise specified in the individual monograph the requirements are met if the quantities of active ingredient(s) dissolved from the dosage forms tested conform to Table 1. Continue testing through the three levels unless the results conform at either S1 or S2. The quantity, Q, is

the specified amount of dissolved active ingredient expressed as a percentage of the labelled content; the 5%, 15% and 25% values in the acceptance table are percentages of the labelled content so that these values and Q are in the same terms.

Table 1

Level Samples tested Acceptance criteriaS1 6 Each value is not less than Q + 5%S2 6 Average value of the 12 dosage units (S1 + S2) is equal to or

greater than Q and no unit is less than Q-15%S3 12 Average value of 24 dosage units (S1 + S2 + S3) is equal to or

greater than Q; not more than 2 units are less than Q - 15%; no unit is less than Q - 25%.

Sustained release dosage forms

Unless otherwise specified in the individual monograph, the requirements are met if the quantities of active ingredient(s) dissolved from the dosage forms tested conform to Table 2. Continue testing through the three levels unless the results conform at either L1 or L2. Limits on the amounts of active ingredient(s) dissolved are expressed in terms of the labelled content. The limits embrace each value of Qi , the amount dissolved at each specified fractional dosing interval. Where more than one range is specified the acceptance criteria apply individually to each range.

Table 2

Level Samples tested Acceptance criteriaL1 6 No individual value lies outside each of the stated ranges and

no individual value is less than the stated amount at the final test time

L2 6 The average value of the 12 dosage units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time; none is more than 10% of the labelled content outside each of the stated ranges; and none is more than 10% of labelled content below the stated amount at the final test time

L3 12 The average value of the 24 dosage units (L1 + L2 + L3) lies within the stated ranges and is not less than the stated amount at the final test time; not more than 2 of the 24 dosage units are more than 10% of labelled content outside each of the stated ranges; not more than 2 of the 24 dosage units are more than 10% of labelled content below the stated amount at the final test time; and none of the 24 dosage units is more than 20% of labelled content below the stated content at the final test time; none of the units are more than 20% of

labelled content outside each of the stated ranges or more than 20% of labelled content below the stated amount at the final test time

Delayed-release dosage forms

Acid stage. Unless otherwise stated in the individual monograph the requirements of this part of the test are met if the quantities, based on the percentage of the labelled content of active ingredient(s) dissolved from the dosage units tested conform to Table 3. Continue testing through the three levels unless the results of both acid and buffer stages conform at an earlier level.

Table 3

Level Samples tested Acceptance criteriaA1 6 No individual value exceeds 10% dissolvedA2 6 Average value of the 12 dosage units (A1 + A2) is not more

than 10% dissolved, and no individual value is greater than 25% dissolved

A3 12 Average value of 24 dosage units (A1 + A2 + A3) is not more than 10% dissolved, and no individual value is greater than 25% dissolved.

Buffer stage. Unless otherwise specified in the individual monograph the requirements are met if the quantities of active ingredients dissolved from the units tested conform to Table 4. Continue testing through the three levels unless the results of both stages conform at an earlier level. The value of Q in Table 4 is the specified total amount of API dissolved in both the acid and buffer stages, expressed as a percentage of the labelled content. The 5%, 15% and 255 values in the table are percentages of the labelled content so that these values and Q are in the same terms.

Table 4

Level Samples tested Acceptance criteriaB1 6 No value is less than Q + 5%B2 6 Average value of the 12 dosage units (B1 + B2) is equal to or

greater than Q, and no unit is less than Q - 15%B3 12 Average value of the 24 dosage units (B1 + B2 + B3) is equal

to or greater than Q; not more than 2 units are less than Q - 15%, and no unit is less than Q - 25%.

Monographs of The International Pharmacopoeia

The following additional statements apply to the individual monographs of The International Pharmacopoeia.

Performance of dissolution test equipment

Periodically verify the performance of the equipment2 utilizing an appropriate mechanical procedure or reference tablet.

2For example, use the mechanical process described in International Standard procedure ASTM 2503-07 or reference tablets such as those available from the United States Pharmacopeia Convention Inc., every 6 –12 months for each individual system.

Test conditions

The following specifications are given in the individual monographs:

• the apparatus to be used;

• the composition and volume of the dissolution medium;

• the rotation speed of the paddle or basket;

• the preparation of the test and reference solutions;

• the time, the method and the amount for sampling of the test solution or the conditions

• for continuous monitoring;

• the method of analysis;

• the limits of the quantity or quantities of active pharmaceutical ingredient(s) required to dissolve within a prescribed time.

Dissolution media

If a buffer is added to the dissolution medium adjust its pH to within ± 0.05 units of the prescribed value.

In specific cases, and subject to approval by the relevant regional or national authority, dissolution media may contain enzymes and/or surfactants. The addition of enzymes may be considered, for example, for formulations containing gelatin in the outer layer when dissolution failures can be ascribed to the cross-linking of this excipient (e.g. hard and soft gelatin capsules).For the testing of preparations containing poorly aqueous-soluble active substances modification of the medium may be necessary. In such circumstances a low concentration of surfactant may be prescribed.

Below are some examples of dissolution media:

• Dissolution buffer pH 1.3, TS

Dissolve 2 g of sodium chloride R in 800 mL of water R, adjust the pH to 1.3 with hydrochloric acid (~70 g/l) TS and dilute to 1000 mL with water R.

• Dissolution buffer pH 2.5, TS

Dissolve 2 g of sodium chloride R in 800 mL of water R, adjust the pH to 2.5 with hydrochloric acid (~70 g/l) TS and dilute to 1000 mL with water R.

• Dissolution buffer pH 3.5, TS

Dissolve 7.507 g of glycine R and 5.844 g of sodium chloride R in 800 mL of water R, adjust the pH to 3.5 with hydrochloric acid (~70 g/l) TS and dilute to 1000 mL with water R.

• Dissolution buffer pH 4.5, TS

Dissolve 6.8 g of potassium dihydrogen phosphate R in 900 mL of water R, adjust the pH to 4.5 either with hydrochloric acid (~70 g/l) TS or sodium hydroxide (~80 g/l) TS and dilute to 1000 mL with water R.

• Dissolution buffer, pH 6.8, TS

Dissolve 6.9 g of sodium dihydrogen phosphate R and 0.9 g of sodium hydroxide R in 800 mL of water R, adjust the pH to 6.8 with sodium hydroxide (~80g/l) TS and dilute to 1000 mL with water R.

• Dissolution buffer, pH 6.8, 0.25% SDS TS

Dissolve 6.9 g of sodium dihydrogen phosphate R, 0.9 g of sodium hydroxide R and 2.5 g of sodium dodecyl sulfate R in 800 mL of water R, adjust the pH to 6.8 with sodium hydroxide (~80g/l) TS and dilute to1000 mL with water R.

• Dissolution buffer pH 7.2, TS

Dissolve 9.075 g of potassium dihydrogen phosphate R in water R to produce 1000 mL (solution A). Dissolve 11.87 g of disodium hydrogen phosphate R in sufficient water R to produce 1000 mL (solution B). Mix 300 mL of solution A with 700 mL of solution B.

• Gastric fluid, simulated, TS

Dissolve 2.0 g of sodium chloride R and 3.2 g of pepsin R in 7.0 mL of hydrochloric acid (~420 g/l) TS and sufficient water R to produce 1000 mL. This test solution has a pH of about 1.2.

• Intestinal fluid pH 6.8, simulated, TS

Mix 77.0 mL of sodium hydroxide (0.2 mol/l) VS , 250.0 mL of a solution containing 6.8 g potassium dihydrogen phosphate R and 500 mL of water R. Add 10.0 g pancreatin R, mix and adjust pH to 6.8 ± 0.1. Dilute to 1000 mL with water R.

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