First Antibiotics Used by Doctors, Penicillin API manufacturers in China

Introduction

Penicillin is an antibiotic, belonging to the beta-lactamase class of drugs. These were the first antibiotics used by doctors. Penicillin is often used for treating infections caused by streptococcus and other gram-positive bacteria. Both branded and generic versions of this drug are available in the market. It is available as an oral tablet (Penicillin V), oral powder for suspension, and IV powder for injection (Penicillin G). Penicillin can typically be used by adults and children over 12 years of age. The standard dosage is between 125 to 250 mg every 6 to 8 hours, however, the exact dosing depends on the type and intensity of the infection being treated. The usual period of treatment with penicillin is between 2 to 10 days, and the exact duration of treatment depends on the infection being treated. (1,2,3)

Branded penicillin is sold by Pfizer as Pfizerpen VK tablet (penicillin V) and Pfizerpen (penicillin G).

Chemical features

• CAS number: 61-33-6

• Molecular structure: 

• Molecular formula: C16H18N2O4S

• Weight: 334.3901 g/mol

• Appearance: Amorphous white powder

• Other physical features: Sparingly soluble in water; insoluble in petroleum ether; soluble in methanol, ethanol, ether, ethyl acetate, benzene, chloroform, acetone (4) 

Penicillin forms and specifications

• Penicillin API powder: Penicillin is sold in its API powder form to be used for the production of other penicillin formulations.

• Penicillin G: penicillin G (benzylpenicillin) is a naturally occurring form of penicillin and is still used clinically. Due to its poor stability in acid, most of penicillin G is broken down as it passes through the stomach. Subsequently., it must be given by an intramuscular injection limiting its usefulness

• Benzathine penicillin G: It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol. Benzathine penicillin G has extremely low solubility, thus, is slowly released from intramuscular injection sites. The drug is then hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower, but much more prolonged than other parenteral penicillins.

• Penicillin V potassium: penicillin V (phenoxymethylpenicillin) is also a naturally occurring form of penicillin. It is given orally and is more resistant to digestive acids than penicillin G. Penicillin V potassium is the potassium salt of penicillin V. (6,8)

Amoxicillin vs penicillin

Antibiotics are usually prescribed in case of a bacterial infection. Amoxicillin or penicillin is one of the commonly prescribed antibiotics, of course depending on how suitable they are for the patient. Both amoxicillin and penicillin are generic antibiotics belonging to a larger class of antibiotics called beta-lactams. They can treat similar bacterial infections of the respiratory tract, genitourinary tract, ear, nose, and throat. Amoxicillin is a broad-range antibiotic which was created by altering the original chemical structure of penicillin to make it more potent. These drugs act by blocking the bacteria’s ability to build and maintain its protective structure, also known as the cell wall, without which the bacteria are unable to survive. It is known that amoxicillin and penicillin can kill different types of bacteria, hence used in different ways. According to a systematic review conducted in 2018, amoxicillin is believed to be better than penicillin for treating community-acquired pneumonia. Results also showed that penicillin is better for treating respiratory tract infections due to its narrow spectrum of coverage. (1,7)

Penicillin manufacturing process

• Production technique

• Fermentation: The technique of fermentation is used for the commercial production of penicillin. Penicillin is produced in a fed-batch process which is carried out aseptically in stainless steel tank reactors having a capacity of 30 to 100 thousand gallons. The process involves two to three initial seed growth phases, which are followed by a fermentation production phase, with a time cycle ranging from 120 to 200 hours.

• Carbon source used during fermentation: Glucose, sucrose, and other crude sugars have been adopted as the carbon sources for this process. Approximately 65% of the carbon is utilized for cellular maintenance, 25% of carbon is used for growth and only 10% is used for penicillin production. Sugar also helps regulate the pH value during the active phase of penicillin production.

• Mini-harvest protocols: Mini harvest protocols are usually employed in the process of fermentation. It involves removing 20-40% of the fermentor contents, replacing it with a fresh sterile medium, and repeating the procedure several times. This does not lead to any yield reduction, in fact, it enhances the total yield of penicillin per fermentor.

• Extraction of penicillin: Penicillin which is excreted into the medium is recovered at the end of the fermentation process. Whole broth extraction is performed at an acidic pH. Solvent extraction of chilled acidified broth is then carried out with amyl, butyl, or isobutyl acetate. 

• Automation during production: Penicillin fermentations currently is highly automated. All the precursors required during the production such as ammonia, sugar, carbon dioxide, oxygen is controlled by monitoring temperature and pH for optimal production of the antibiotic. The pH should ideally be between 6.4 and 6.8 during the active production phase 

• Improved quantity of anti-biotic using new strain and latest, automated technology: Penicillin was initially made using the fungus Penicillium notatum. The process yielded only one milligram of penicillin per cubic decimeter. However, today, a different species of fungus is used (Penicillium chrysogenum) which has improved the yield of penicillin to 50 grams per cubic decimeter. Improvements in modern methods of production have significantly increased the yield of penicillin and decreased the production cost. Penicillium chrysogenum strains used for commercial production are now grown using submerged culture in 50,000-gallon stainless steel tanks, which are constantly agitating and aerated. These industrial strains can produce 40-50 grams of penicillin per liter of culture, with a 90% recovery yield.  To achieve these production rates, modern penicillium strains have been hugely modified genetically and at a cellular level. (2)

Uses of penicillin 

Many derivatives of penicillin have now been developed and they can inhibit more types of bacteria than the original penicillin itself can. Nevertheless, penicillin itself is active against Streptococci, including Streptococcus pneumoniae, Listeria, Neisseria gonorrhoeae, Clostridium, Peptococcus, Peptostreptococcus, Penicillin G benzathine may also be used to prevent certain bacterial infections such as rheumatic fever. It is important to note that most staphylococci now are resistant to penicillin. (2)

Side effects of penicillin

• The most common side effects of taking penicillin are: 

• Diarrhea

• Nausea

• Headache

• Skin rashes

• Hives

Some people may also have a penicillin allergy. These allergic reactions typically cause hives, wheezing, and/or swelling, particularly of the face. (3) If penicillin has been injected, a patient may experience pain at the injection site, nausea, or vomiting. (9)

Penicillin API manufacturers in China 

According to an article published in 2018 August, the worldwide sales of penicillin and other beta-lactam antibiotics were greater than USD 15 billion per year, despite penicillin costs being at an all-time low. Penicillin now costs about USD10 per kg versus USD 300 per kg in the 1950s. Europe is the major producer of beta-lactam antibiotics; however, newer manufacturing facilities are seen to relocate to China where energy costs and labor are lower. Various manufacturers around the globe follow cGMP guidelines for producing penicillin. Some leading medical supplies manufacturers from China are:

• Suzhou Erye Pharmaceutical Co., Ltd.: Suzhou Erye Pharmaceutical Co., Ltd. was founded in 1946. The company has production lines of APIs, cephalosporins for injection, penicillin for injection, freeze-dried powder for injection, and oral dosages.

• North China Pharmaceutical Co., Ltd.: NCPC is a leading pharmaceutical manufacturer in China. Their capacity for production of penicillin, streptomycin, 6-APA, amoxycillin, cephradine, vitamin B100 is in the lead worldwide.

• Sinopharm Weiqida Pharmaceutical Co., Ltd.: Sinopharm Weiqida Pharmaceutical Co Ltd. is a comprehensive pharmaceutical manufacturer, invested and held by China National Pharmaceutical Group Corp. They produce cephalosporin, penicillin, and potassium clavulanate products starting from Intermediates, APIs until Formulations.

• SHANDONG LUKANG PHARMACEUTICAL CO., LTD.: Shandong Lukang Pharmaceutical Co Ltd (LKPC) was established in 1966. It is a leading manufacturer of antibiotic products in China. They focus on R&D, production, and marketing of APIs, pharmaceutical intermediates, and finished products for human, veterinary, and agricultural use.

• CSPC Pharmaceutical Group Ltd.: CSPC Pharmaceutical Group is involved in the research, development, manufacturing, and sale of pharmaceutical products. CSPC produces both APIs and formulations. API products include penicillin, cefalosporins, synthetic vitamins, caffeine, and ranitidine.

You can also find details around more suppliers for penicillin API in bulk at PharmaSources.com. PharmaSources.com is one of the leading and trustworthy vertical e-commerce online pharmaceutical marketplaces. It provides information on quality pharmaceutical products and suppliers for its customers and delivers services to 90,000+ active members. The services are provided globally, across 211 countries and regions. PharmaSources.com sells over 1,600,000 products in 30 major pharmaceutical categories across the supply chain. (8,10)

Sources:

1.     https://www.singlecare.com/blog/amoxicillin-vs-penicillin/

2.     https://www.medicinenet.com/penicillins-injection/article.htm

3.     https://www.medicalnewstoday.com/articles/216798#resistance

4.     https://pubchem.ncbi.nlm.nih.gov/compound/Penicillin#section=Molecular-Formula

5.     https://www.britannica.com/science/penicillin

6.     https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050141s231lbl.pdf

7.     https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163205/

8.     https://www.news-medical.net/health/Penicillin-Production.aspx

9.     https://www.webmd.com/drugs/2/drug-3781/penicillin-g-benzathine-intramuscular/details

10.   www.Pharmasources.com