Caterina Funaro IMA Active Process Laboratory Manager and Coating Expert 

Pain is a complex sensation that plays a crucial role in our daily life experience. Aching is a real health problem of epidemic proportions with 15% to 25% of people reporting to suffer from pain most days or every day; pain increases with age and with low socioeconomic status. Persistent, intense pain can impair a person’s mental and physical well-being. Understanding the mechanisms connected to this experience is fundamental to improve therapies and quality of life.

Acute and chronic pain are different clinical entities. Acute pain is viewed as a physiological, time-limited, protective response to a specific injury that resolves with healing. In contrast, chronic pain may be considered a ‘disease state in its own right’ according to the European Pain Federation.

By exploring the neurobiology of pain, it is possible to analyse how our nervous system processes and perceives painful signals. The process begins with the transmission of signals through nerve pathways. Nociceptors, receptors specialized in detecting tissue damage, send signals to the spinal cord, where the first processing of pain occurs. From here, the information is transmitted to the brain, which interprets and gives meaning to the signal.

Modern research has brought to light several theories about the origins of chronic pain, from neuroplastic changes to chronic inflammation. Recent discoveries have highlighted the crucial role of neurotransmitters and brain pathways involved in pain perception.

Among the traditional approaches, analgesic drugs and physiotherapy stand out, while among the new frontiers, we can mention gene therapy and deep brain stimulation. Each approach has pros and cons and can reveal potential benefits and limitations.

Musculoskeletal pain conditions are very often age-related, leading contributors to chronic pain and pain-related disability, which are expected to rise with the rapid aging of the global population. Unfortunately, current medical treatments provide only partial relief. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are effective in young and otherwise healthy individuals, but are often contraindicated in elderly and frail patients.  As a result of its favourable safety and tolerability record, paracetamol has long been the most common drug for treating pain.

Paracetamol has been assessed in different conditions and demonstrated therapeutic efficacy on both acute and chronic pain. It is active as a single agent and is additive or synergistic with NSAIDs and opioids, improving their efficacy and safety. However, a lack of significant efficacy and hepatic toxicity have also been reported. Fast-dissolving formulations of paracetamol provide superior and more extended pain relief that is similar to intravenous paracetamol.

PHARMACOKINETICS AND PHARMACODYNAMIC MECHANISM OVERVIEW

Here is an overview of the different mechanisms of action of some common pain medications, including a mention of acetaminophen. Each of these drugs has a specific approach to treating pain, and the choice depends on the nature and severity of the pain, as well as the patient's medical condition.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen inhibit the COX enzyme, reducing the production of prostaglandins. This leads to a decrease in inflammation, pain and fever. NSAIDs act both peripherally, in the tissues, and centrally in the nervous system.

Opioids, such as morphine and oxycodone work by binding to opioid receptors in the central nervous system. This blocks the transmission of the pain signal, reducing pain perception. Opioids are often used to treat severe pain, but they can cause side effects and addiction.

Anticonvulsant drugs, such as gabapentin and pregabalin modify the activity of nerve cells in the central nervous system, reducing neuronal hyperactivity associated with neuropathic pain.

Paracetamol (Acetaminophen) acts mainly in the central nervous system to reduce the perception of pain and to lower fever. Despite being widely used, its exact mechanism is not fully understood. Paracetamol is believed to act selectively on the COX (cyclooxygenase) enzyme in the brain, reducing the production of prostaglandins, substances involved in the transmission of pain signals.

Unlike non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol has limited action on inflammation and acts mainly as an analgesic and antipyretic.

Some of the emerging trends in pain medication includes the development of Non-Opioid Analgesics: due to concerns related to addiction and side effects of opioids, there was growing interest in developing safer and more effective non-opioid analgesics.

Approaches involving combinations of more than one drug to target different pain sources can be also very effective: for example, the synergistic use of non-opioid analgesics with anti-inflammatory drugs.

Research focuses on drugs that specifically target neuropathic pain, including some anticonvulsants and antidepressants.

Other approaches aim to modulate specific nerve receptors involved in pain perception, with the aim of reducing the painful sensation.

The growing use of innovative technologies, such as neuromodulation, to treat chronic pain includes implantable devices that stimulate specific nerves to reduce pain.

At the same time, great interest is rising on customized medicines: personalized drugs adapted to the individual characteristics of patients to maximize effectiveness and reduce side effects.

Paracetamol has been used for a long time for the treatment of headache and migraine. Using the American Academy of Neurology criteria to develop guidelines, the American Headache Society considered oral paracetamol effective with a level of evidence A (established as effective) when used alone or in combination with aspirin for non-incapacitating attacks of migraine (effective), with a level B (probably effective) when used in combination with codeine or tramadol, and with a level C (possibly effective) when used in combination with butalbital.

PRODUCTION METHODS IN PHARMACEUTICAL APPLICATION

The excellent tolerability of therapeutic doses of paracetamol is a major factor in the very wide use of the drug: manufacturing of solid oral dose forms including tablets, capsules, granules as well as syrup and suppositories is of major interest in pharmaceutical field. The production of pain killers, including paracetamol, involves several manufacturing methods and steps.Most common methods are direct compression followed by pan coating.

These methods are preferred because relatively simple and efficient, reducing the number of steps in the manufacturing process; furthermore they require less equipment than other methods.

Recognised as the most stable and economic pharmaceutical forms, tablets are produced by direct compression in general as instant release (IR) formulation with 500 or 1000 mg as API content. Direct compression represents a straight way to hit the target of obtaining high tablet quality with only one step: from powder to tablet without passing through granulation. However, this approach hides several challenges: the acetominophen is high-dosed within the formulation and it has a medium tendency of intra-particle electrostaticity, adhesivity and cohesivity. This allows fine-tuning in terms of chosen tableting process parameters and settings that requires both knowledge than equipment flexibility.

The resulting coating protects the drug from moisture, masks unpleasant taste and allows the controlled release of the active ingredient into the digestive system. Due to the tablets’ high mass, coating can also help swallowing and patient compliance.

The safety and tolerability record and the safety advantages of paracetamol over other classes of NSAIDs and opioid analgesics have been among the reasons for its ongoing presence or inclusion in pain treatment guidelines by expert panels.

Notably, several reports support the equivalent safety and efficacy profile of both oral and intravenous administrations. This conclusion is particularly relevant, suggesting that paracetamol may be used equally through both administration routes in several clinical cases, intravenous in an emergency and oral to treat chronic pain conditions.

For those reasons, paracetamol was selected for a case study exploring its manufacturing challenges.

Paracetamol tablet production by direct compression

The formulation chosen contains 90% of paracetamol and, before tableting, the blend was passed through a 1.2mm sieve to homogenize the particle distribution and increase powder flowability. This preliminary step is fundamental when approaching tableting through direct compression: it removes lumps and agglomeration before loading powder into feeder.

Large-scale industrial, double-side rotary tablet press (PREXIMA 800, IMA Italy) is used as equipment to enhance production. It was equipped with Euro-D turret hosting 53 stations and biconvex oblong Euro-D punches.

Production was increased consistently, respectively at 318,000 tablets per hour (tph), 381,600 tph and 508,800 tph (test 1, test 2 and test 3, 

At the end, tablets were checked from a technological point of view to confirm compliance with quality required by Pharmacopeia: analysis focused on weight and hardness variation comparing all the trials with each other.

Table 1: tableting process parameters for paracetamol production in PREXIMA 800

As announced, correct upstream processes allow for a smooth tableting process: tablets produced always fit the quality required by the Pharmacopeia thanks to the combination of good sieving and mechanical choices on the tablet press itself.

Close attention was given to weight variation and its relative standard deviation over the time: good and reproducible results were achieved for both equipment sides and at all the tablet press speeds explored (

Figure 1: weight variation of test 1, test 2 and test 3 in PREXIMA 800

This all-in graph evidences both sides of PREXIMA 800 for each test: comparing the two sides, the trend is always comparable and relative standard deviation is less than 1%, confirming process stability independently of the chosen tablet press speed.

To confirm and reinforce the results, tablet strength was also monitored: the robust structure of PREXIMA 800 maintains its stability regardless of peripheral speed achieved (

Figure 2: tablet strength variation of test 1, test 2 and test 3 in PREXIMA 800

As before, the same approach was pursued to evaluate tensile strength: this all-in graph evidences both sides of PREXIMA 800 for each test. Tablet hardness is reproducible and comparable monitoring the two sides of the same tests and it slightly decreases when speeding up the machine, showing stability and robustness of the process performed.

A set of trials was conducted to verify process feasibility with different batch sizes (meaning different drum filling percentage) in a perforated pan coater IMA Perfima 200 – 250-litre capacity. Oblong shaped cores containing paracetamol were coated with Opadry OY-S 13% w/w aqueous suspension. The suspension amounts were calculated with respect to different batches, as reported in the table below. Being 250 L the maximum workable batch of the pan coater and 0.68 kg/L the tablet bulk density, the respective core mass was calculated as volume multiplied by density. Target weight gain including losses was calculated to be 3.75%

Depending on batch size, operational parameters were adapted to different tablet loadings as reported in table below.

Table 3: operational parameters for a minimum coater loading of 42.5 kg (62.5 L)

Table 4: operational parameters for a maximum coater loading of 170 kg (250 L)

In all trials, very good tabletability and optimal coating quality were achieved in terms of core characteristics, coating surface and final appearance, demonstrating the actual possibility of producing paracetamol tablets in different operative conditions.

In-depth understanding of the neurobiology of pain is crucial to develop more targeted and effective treatments. The combination of traditional and innovative approaches can pave the way for more comprehensive and personalized pain management. Research continues to offer new perspectives, pointing to a future in which suffering can be addressed more effectively. In the meantime, pharmaceutical companies are trying to work on the increasingly robust and controlled production of drugs (such as paracetamol) that guarantees high quality standards and process reproducibility.

L. Kalantzi et al., Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Acetaminophen (Paracetamol), Journal of Pharmaceutical Sciences, Vol 95, No. 1 January 2006

F. Giatti, F. Ferrini, how to enhance tableting production with a paracetamol based formulation, 

https://ima.it/pharma/paper/how-to-enhance-tableting-production-with-a-paracetamol-based-formulation/

Freo U, Ruocco C, Valerio A, Scagnol I, Nisoli E. Paracetamol: A Review of Guideline Recommendations. J Clin Med. 2021 Jul 31;10(15):3420. doi: 10.3390/jcm10153420. PMID: 34362203; PMCID: PMC8347233.

Blyth FM, Briggs AM, Schneider CH, Hoy DG, March LM. The Global Burden of Musculoskeletal Pain-Where to From Here? Am J Public Health. 2019 Jan;109(1):35-40. doi: 10.2105/AJPH.2018.304747. Epub 2018 Nov 29. PMID: 30495997; PMCID: PMC6301413.

Caterina Funaro IMA Active Process Laboratory Manager and Coating Expert

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